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2.5: Poliploidiya xromosomalarning butun to'plamidagi o'zgarishlardan kelib chiqadi - Biologiya

2.5: Poliploidiya xromosomalarning butun to'plamidagi o'zgarishlardan kelib chiqadi - Biologiya


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Agar siz (PageIndex{15}) rasmiga qaytsangiz, ko'pchilik hayvonlar va ko'pchilik eukaryotik genetik model organizmlar kabi odamlarda har bir autosomaning ikkita nusxasi borligini ko'rishingiz mumkin. Bu holat deyiladi diploidiya. Aksincha, ko'plab o'simlik turlari va hatto bir nechta hayvonlar turlari mavjud poliploidlar. Bu shuni anglatadiki, ular ikkitadan ortiq xromosoma to'plamiga ega va shuning uchun har bir hujayrada har bir xromosomaning ikkitadan ortiq homologlari bor.

Yadro tarkibi butun xromosoma to'plami tomonidan o'zgarganda, biz buni ploidlikning o'zgarishi deb ataymiz. Gametalar haploid (1n), shuning uchun ko'pchilik hayvonlar ikkita haploid gametning birlashishi natijasida hosil bo'lgan diploid (2n) dir. Biroq, ba'zi turlar monoploid (1x), triploid (3x), tetraploid (4x), pentaploid (5x), geksaploid (6x) yoki undan yuqori bo'lishi mumkin.

Ploidiyaning belgilanishi

Poliploidlarni tasvirlashda biz "harfidan foydalanamiz.x” (“n” emas) ploidlik darajasini aniqlash uchun. A diploid 2x, chunki ikkita asosiy xromosoma to'plami mavjud va a tetraploid 4x, chunki u to'rtta xromosoma to'plamini o'z ichiga oladi. Poliploidlarni muhokama qilishda aniqlik uchun genetiklar ko'pincha "x" belgisini ushbu bobda ilgari aniqlangan "n" belgisi bilan birlashtiradi. Shunday qilib, ham diploidlar, ham poliploidlar uchun "n" - bu gametadagi xromosomalar soni, "2n" - urug'lantirilganidan keyingi xromosomalar soni. Diploid uchun n = x va 2n = 2x. Lekin tetraploid uchun n=2x va 2n=4x va geksaploid uchun n=3x va 2n=6x.

Erkak asalarilar monoploiddir

Monoploidlar, faqat bitta to'plam bilan, odatda, ko'pchilik turlarda sezilmas, ammo gimenopteralarning ko'p turlarida (asalarilar, ari, chumolilar) erkaklar monoploid bo'lib, urug'lanmagan tuxumdan rivojlanadi. Bu erkaklar gametalar uchun mayozga uchramaydilar; mitoz sperma hosil qiladi. Urg'ochilar diploid (urug'langan tuxumdan) bo'lib, mayoz orqali tuxum ishlab chiqaradi. Bu haploid-diploid jinsini aniqlash tizimi uchun asosdir (X/Y xromosoma tizimi emas). Urg'ochi asalarilar diploid (2n = 32) bo'lib, tuxum (n = 16) sperma bilan urug'lantirilganda (n = 16) hosil bo'ladi. Agar tuxum urug'lanmagan bo'lsa, u hali ham rivojlanishi mumkin va natijada n = 16 erkak dron bo'ladi. Erkaklar haploid (gamet bilan bir xil xromosomalarga ega bo'lgani uchun) yoki monoploid (chunki ular bitta xromosoma to'plamiga ega) deb ta'riflanadi. Urg'ochilar mayoz orqali tuxum ishlab chiqaradilar, erkaklar mitoz orqali sperma hosil qiladi. Jinsni aniqlashning bu shakli erkaklarga qaraganda ko'proq reproduktiv ish uchun zarur bo'lgan ayollarni-ishchilarni ishlab chiqaradi (2-18-rasm).

Rasm (PageIndex{18}):Ishchi, urg'ochi va diploid bo'lgan evropalik asal kastasini. Erkak dronlar haploiddir. (Vikipediya-J. Severns-PD)

Poliploidlar barqaror yoki steril bo'lishi mumkin

Diploidlar (2n=2x) kabi barqaror poliploidlar odatda har bir xromosomaning juft sonli nusxalariga ega: tetraploid (2n=4x), geksaploid (2n=6x) va hokazo. Buning sababi meyozni ko'rib chiqishdan aniq. Meyozning maqsadi genetik materialning yig'indisini ikki baravar kamaytirish ekanligini eslab, meyoz xromosomalar to'plamining juft sonini teng ravishda ajratishi mumkin, ammo toq sonni emas. Shunday qilib, toq sonli xromosomali poliploidlar (masalan, triploidlar, 2n=3x) bepusht, hatto ular sog'lom bo'lsa ham.

Barqaror poliploidlarda meyozning mexanizmi asosan diploidlardagi kabi: metafaza I davrida gomologik xromosomalar bir-biri bilan juftlashadi. Turlarga qarab, barcha homologlar metafazada yoki bir nechta alohida juftlikda birlashtirilishi mumkin. Masalan, tetraploidda ba'zi turlar paydo bo'lishi mumkin tetravalentlar bunda har bir xromosomadan to'rtta homolog bir -biriga mos keladi, yoki ikkita juft homolog ikkita bivalent hosil qilishi mumkin. E'tibor bering, chunki mitoz gomologik xromosomalarning juftlanishini o'z ichiga olmaydi, mitoz diploidlar, juft sonli poliploidlar va toq sonli poliploidlarda bir xil darajada samarali bo'ladi.

Ko'pchilik ekin o'simliklari hexaploid yoki oktoploiddir

Poliploid o'simliklar diploidlarga qaraganda kattaroq va sog'lom bo'ladi. Oziq-ovqat do'konlarida sotiladigan qulupnaylar keladi oktoploid (8x) shtammlari va yovvoyi diploid shtammlari tomonidan hosil qilingan qulupnaydan ancha katta. Misol tariqasida nonli bug'doyni keltirish mumkin hexaploid (6x) kuchlanish. Bu tur boshqa uchta bug'doy turining kombinatsiyasidan olingan. T. monokok (xromosoma to'plamlari = AA), T. sersii (BB) va T. tauschii (DD). Ushbu xromosoma to'plamlarining har biri 7 ta xromosomaga ega, shuning uchun diploid turlari 2n = 2x = 14 va non bug'doyi 2n = 6x = 42 va AABBDD xromosoma to'plamlariga ega. Non bug'doyi hayotiydir, chunki har bir xromosoma mitoz paytida mustaqil harakat qiladi. Tur ham unumdor, chunki meioz paytida A xromosomalari boshqa A xromosomalari bilan bog'lanadi va hokazo. Shunday qilib, hatto poliploidda ham homolog xromosomalar teng ravishda ajralib chiqishi va gen muvozanatini saqlashi mumkin.

Banan, tarvuz va boshqa urugʻsiz oʻsimliklar triploiddir

Oziq -ovqat do'konlarida topilgan banan Cavendish deb nomlangan urug'siz navdir. Ular a triploid deb ataladigan normal diploid turning xilma-xilligi (xromosoma to'plamlari = AAA). Muso acuminata (AA). Kavendish o'simliklari yashovchan, chunki mitoz sodir bo'lishi mumkin. Ammo ular sterildir, chunki meioz I davrida xromosomalar to'g'ri juftlasha olmaydi. I profilaktika davrida har bir xromosomaning uchta nusxasi bir-biri bilan "juftlashishga" harakat qiladi. Meyozda xromosomalarning to'g'ri segregatsiyasi muvaffaqiyatsiz bo'lganligi sababli, urug'lar hosil bo'lmaydi va natijada tupurish uchun urug'lar yo'qligi sababli yeyish osonroq bo'lgan meva hosil bo'ladi. Urug'siz tarvuzlar ( ( PageIndex {19} ) rasmida) shunga o'xshash tushuntirish mavjud.

Rasm (PageIndex{19}): Urug'siz tarvuz triploid bo'lib, tanasida oq, uzilgan urug'lar bor. (Flickr-Darvin Bell-CC: AN)

Agar triploidlar urug' hosil qila olmasa, qanday qilib biz etishtirish uchun etarli triploid shaxslarni olamiz? Javob o'simlik turiga bog'liq. Ba'zi hollarda, masalan, banan, o'simlikni aseksual tarzda ko'paytirish mumkin; yangi avlodni oddiygina triploid o'simlikning so'qmoqlaridan o'stirish mumkin. Boshqa tomondan, urug'siz tarvuz urug'lari jinsiy yo'l bilan ishlab chiqariladi: tetraploid tarvuz o'simliklari diploid tarvuz o'simliklari bilan kesishadi. Tetraploid ham, diploid ham to'liq fertil bo'lib, mos ravishda ikkita (1n = 2x) yoki bitta (1n = 1x) xromosomalar to'plamiga ega gametalar hosil qiladi. Bu gametalar birlashib ketadigan mitozning bir necha davri orqali kattalar o'simlikiga aylanishi mumkin bo'lgan zigotani (2n = 3x) hosil qilish uchun birlashadi.

Poliploidlar hajmi odatda diploid qarindoshlaridan kattaroqdir ( ( PageIndex {20} rasm)). Bu xususiyat oziq -ovqat o'simliklarida keng qo'llaniladi. Masalan, siz iste'mol qiladigan qulupnaylarning ko'pchiligi diploid emas, balki oktoploid (8x).

Hayvonlarda poliploidiya kam uchraydi, asosan pastki shakllar bilan chegaralanadi, ular ko'pincha partenogenez bilan ko'payadi.

Kredit: www.jamesandthegiantcorn.com/wp-content/uploads/2009/11/strawberries2.jpg


Poliploidiya

Poliploid organizmlar - bu hayvonlar, qo'ziqorinlar va o'simliklarning somatik va germlin hujayralarida ikkitadan ortiq xromosomalar to'plamiga (har bir ota -onadan yoki ajdoddan) ega bo'lgan eukaryotlar. Alohida hujayralar yoki hujayra turlarining poliploidiyasi (endopoliploidiya), xromosomalarning hujayra bo'linishisiz ko'payishidan kelib chiqadi, organizmlarning normal (masalan, sekretor hujayralar) yoki g'ayritabiiy (masalan, ko'plab saraton) rivojlanishida ishtirok etadi. Poliploidiya yoki "butun genomning takrorlanishi"-genom evolyutsiyasi va spetsifikatsiyasining muhim belgisidir va ko'pchilik o'simliklar va hayvonlarning nasl-nasablari o'zlarining evolyutsion tarixida shunday takrorlanishlarning turlarini o'z ichiga oladi. Ko'pgina o'simlik turlari, xususan, qadimgi butun genomli takrorlanishlar va yaqinda kelib chiqqan polploidiya hodisalariga ega. Poliploid shaxslar vaqti-vaqti bilan eukaryotik organizmlarning barcha guruhlarida noto'g'ri meyoz, urug'lanish yoki hujayra bo'linishi natijasida topiladi, ammo o'z-o'zidan paydo bo'lgan hayvonlar poliploidlarining ko'pchiligi daxlsizdir. Poliploidlar eksperimental tarzda kolxitsin kabi kimyoviy moddalar bilan ishlov berish yoki diploid yadrolarining birlashishi natijasida hosil bo'lishi mumkin. Ko'pgina poliploidlar, ayniqsa o'simliklar orasida, normal rivojlanadi va poliploidiyaning tabiatiga qarab, steril bo'lishi mumkin yoki yashovchan gametalarni beradigan oddiy diploiddan farq qilmaydigan meiozga uchraydi.


Ploidiyani boshqaruvchi uyali va molekulyar mexanizmlar

Romain Donne. Chantal Desdouets, Hayot fanlari bo'yicha mos yozuvlar modulida, 2018 yil

Xulosa

Poliploidiya - bu diploid hujayra yoki organizm qo'shimcha xromosomalar to'plamini oladigan holat. Poliploidiya o'simliklarga qaraganda sutemizuvchilarda kam tarqalgan bo'lsa -da, poliploid hujayralar turli to'qimalarda hosil bo'ladi. Poliploidiya normal rivojlanish jarayonida muhim rol o'ynaydi va inson kasalliklariga ham hissa qo'shishi mumkin. Poliploid hujayralar abortiv hujayra siklidan keyin (endoreplikatsiya, sitokinez etishmovchiligi, mitotik sirpanish) yoki hujayra-hujayra sintezidan keyin paydo bo'lishi mumkin. Ushbu sharh hujayra tsikli va uning nazorat punktlarini tashkil qilishni davom ettiradi va poliploid hujayralarni hujayra va molekulyar darajada ishlab chiqaruvchi mexanizmlar haqida umumiy ma'lumot beradi.


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Poliploidlarga chidamlilik

Poliploidlar keng tarqalgan. Juda kam mexanizmlar bir zumda spetsifikatsiyaga olib kelishi mumkin, poliploidizatsiya ulardan biridir. Poliploidiya bo'yicha spetsifikatsiya ilmiy jamiyatda mashhur mavzuga aylandi. Ba'zi sabablarga ko'ra ba'zi guruhlar toqat qiladilar, ba'zilari intiladilar, boshqalari esa poliploidizatsiyaga qat'iyan qarshi. Oxirgi poliploidlanish hodisalari umurtqali hayvonlar kabi guruhlarda deyarli kuzatilmagan, lekin angiospermlar kabi o'simlik guruhlarida juda mashhur. Odamlar kabi yuqori umurtqali hayvonlarda poliploidlar kuchli tanlanadi. Darhaqiqat, odamlarda o'z -o'zidan abort qilishning 10% zigotalarda poliploidiya natijasida sodir bo'lgan deb taxmin qilinadi. Shartnomada, angiospermlarning kamida 50% poliploidlardir.

Shunisi e'tiborga loyiqki, juda xilma -xil oilalarda poliploidlar juda ko'p.


Minnatdorchilik

Y.V.d.P. va K.M. Belgiya, Gent universitetining “Bioinformatika: nukleotidlardan tarmoqlarga” (no. 01MR0310W) koʻp tarmoqli tadqiqot hamkorligini tan oling. Y.V.d.P. Yevropa Tadqiqot Kengashining 322739 – DOUBLEUP ilg‘or grant kelishuvi doirasida Yevropa Ittifoqining Yettinchi doiraviy dasturi (FP7/2007-2013) tomonidan moliyalashtirilganligini tan oladi. K.M. Wetenschappelijk Onderzoek - Flanders (FWO15/PRJ/396) fondlarining ovozini qo'llab -quvvatlaydi. Ayniqsa, yordamchi munozaralar uchun R. Lohausga va 3 -rasmni taqdim etgan P. Novikovaga alohida rahmat. Y.V.d.P., E.M. va K.M. shuningdek, Pretoriya universitetiga, Janubiy Afrikaga umumiy qo'llab-quvvatlash uchun rahmat. Mualliflar ishi e'tibordan chetda qolgan yoki kosmik cheklovlar tufayli kiritilmagan ko'plab tadqiqotchilardan kechirim so'rashadi. Nihoyat, mualliflar to'rtta noma'lum sharhlovchiga o'z sharhlari va takliflari uchun minnatdorchilik bildiradilar, bu sharhni yaxshilashga katta yordam berdi.


4 javob 4

Ajoyib savol, va tarixan ko'p taxminlar bo'lgan va hozircha noto'g'ri ma'lumotlar ko'p. Men birinchi navbatda boshqa foydalanuvchilar tomonidan berilgan ikkita javobga to'xtalib o'taman, ular ikkalasi ham noto'g'ri, lekin tarixan olimlar tomonidan taklif qilingan. Keyin men hozirgi tushunishni tushuntirishga harakat qilaman (bu oddiy yoki to'liq emas). Mening javobim to'g'ridan -to'g'ri adabiyotlardan, xususan Mable (2004) dan olingan bo'lib, u o'z navbatida Linnean jamiyatining biologik jurnalining 2004 yilgi maxsus sonining bir qismi bo'lib, bu mavzuga bag'ishlangan.

"Jinsiy" javob.

1925 yilda HJ ​​Myuller mashhur maqolasida bu savolga javob berdi: "Nega hayvonlarda poliploidiya o'simliklardan ko'ra kam uchraydi" (Myuller, 1925). Myuller o'simliklarda poliploidiya tez-tez, lekin hayvonlarda kamdan-kam kuzatiladigan hodisani qisqacha tasvirlab berdi. Uning so'zlariga ko'ra, tushuntirish oddiy edi (va Metyu Piziakning javobida tasvirlanganiga taxminan):

Odatda, hayvonlarning ikkita jinsi bor, ular ajratish va kombinatsiyaning diploid mexanizmini o'z ichiga olgan jarayon orqali farqlanadi, o'simliklar-hech bo'lmaganda yuqori o'simliklar-odatda germafrodit.

Keyin Myuller mexanizmning uchta izohini ishlab chiqdi:

  1. U triploidiya odatda xromosoma duplikatsiyasining oraliq bosqichi deb taxmin qilgan. Bu muammolarga olib keladi, chunki ko'pchilik hayvonlarning jinsi xromosomalar nisbati bilan aniqlansa (Drosophila kabi), triploidiya bepushtlikka olib keladi.
  2. Tetraploid tasodifan yaratilgan kamdan -kam hollarda, u diploidlar bilan ko'payishi kerak edi va bu (ehtimol steril) triploidga olib keladi.
  3. Agar tasodifan ikkita tetraploid paydo bo'lib, juftlashsa, ular ahvolga tushib qolishi mumkin edi, chunki, dedi u, ularga tasodifiy jinsiy xromosomalar ajratiladi va bu hayotga yaroqsiz avlodlarning ko'payishiga olib keladi va shu sababli poliploidlar chizig'iga olib keladi. diploid bilan raqobatlasha oladi.

Afsuski, birinchi ikki nuqta poliploidlar haqida to'g'ri faktlar bo'lsa-da, uchinchi nuqta noto'g'ri. Myullerning tushuntirishidagi asosiy kamchilik shundaki, bu faqat xromosoma nisbati bo'yicha jinsini aniqlaydigan hayvonlarga taalluqlidir, biz aniqlaganimizdek, hayvonlar nisbatan kam. 1925 yilda hayotni tizimli o'rganish nisbatan kam edi, shuning uchun biz o'simlik yoki hayvon taksonining qaysi qismi poliploidiyani ko'rsatishini bilmas edik. Myullerning javobida nima uchun ko'pchilik hayvonlar tushuntirilmagan, masalan. Y-dominant jinsni aniqlashga ega bo'lganlar nisbatan kam poliploidiyani namoyon qiladi. Myullerning javobini inkor etuvchi yana bir dalil shundan iboratki, aslida poliploidiya ikki qavatli o‘simliklarda (alohida erkak va urg‘ochi o‘simliklarga ega bo‘lganlar, masalan, Vestergaard, 1958) juda keng tarqalgan, Myuller nazariyasi esa, bu guruhdagi tarqalish hayvonlardagi kabi past bo‘lishi kerakligini taxmin qiladi. .

"Murakkablik" javobi.

Tarixiy ta'sirga ega bo'lgan yana bir javob - bu Daniel Stendjening bergan javobidir va ko'p yillar davomida turli olimlar tomonidan berilgan (masalan, Stebbins, 1950). Bu javobda aytilishicha, hayvonlar o'simliklarga qaraganda murakkabroq, shuning uchun ularning molekulyar mexanizmlari ancha yaxshi muvozanatlangan va bir nechta genom nusxalariga ega bo'lganligi sababli bezovtalanadi.

Bu javob ikki asosiy fakt asosida qat'iyan rad etilgan (masalan, Orr, 1990). Birinchidan, poliploidiya hayvonlarda g'ayrioddiy bo'lsa -da, u sodir bo'ladi. Germafrodit yoki partenogenetik ko'payish usullariga ega bo'lgan turli hayvonlar ko'pincha poliploidiyani ko'rsatadi. Shuningdek, sutemizuvchilar poliploidiyasiga misollar bor (masalan, Gallardo va boshqalar, 2004). Bundan tashqari, poliploidiya hayvonlarning keng turlarida sun'iy ravishda qo'zg'atilishi mumkin, hech qanday zararli ta'sir ko'rsatmaydi (aslida u ko'pincha gibrid kuchga o'xshash narsalarni keltirib chiqaradi Jekson, 1976).

Shuni ham ta'kidlash joizki, 1960-yillardan beri Susumo Ohno (masalan, Ohno va boshq. 1968 Ohno 1970 Ohno 1999) umurtqali hayvonlar evolyutsiyasi ko'p genomli takrorlanish hodisalarini (kichik dublikatlardan tashqari) o'z ichiga oladi, degan taklifni ilgari surmoqda. Furlong & amp Holland (2004) da ko'rib chiqilgan ushbu g'oyani tasdiqlovchi muhim dalillar mavjud. Agar rost bo'lsa, bu hayvonlarning murakkabligi (o'zi katta va mening nazarimda noto'g'ri, taxmin) poliploidiyaga to'sqinlik qilmasligini yana bir bor ta'kidlaydi.

Zamonaviy sintez.

Va shunday qilib, bugungi kungacha. Mable (2004) da ko'rib chiqilganidek, hozir shunday deb o'ylashadi:

  • Poliploidiya - bu muhim biologik xilma -xillik uchun javobgar bo'lgan muhim evolyutsion mexanizm.
  • Poliploidiya hayvonlarda ham, o'simliklarda ham osonlik bilan paydo bo'ladi, lekin reproduktiv strategiya genomning ko'payishi natijasida fitnesning pasayishiga emas, balki ma'lum sharoitlarda tarqalishiga to'sqinlik qilishi mumkin.
  • Poliploidiya hayvonlarda oldindan kutilganidan ko'ra ko'proq tarqalgan bo'lishi mumkin va ma'lumotlarning nomutanosibligi yovvoyi namunalarning katta populyatsiyalarining sitogenetikasi (ya'ni xromosomalarni hisoblash) botanikada juda keng tarqalgan va zoologiyada juda kam uchraydigan amaliyot ekanligidan kelib chiqadi.

Bundan tashqari, hozirda ploidiya bilan bog'liq bir nechta yangi shubhali omillar mavjud bo'lib, ular hozirda tekshirilmoqda:


2.5: Poliploidiya xromosomalarning butun majmuasidagi o'zgarishlardan kelib chiqadi - biologiya

Sharh maqolasi - Saraton immunologiyasi jurnali (2020) 2-jild, 4-son

Poliploidli saraton hujayralariga hujum qilish strategiyasi

Jing Chjan 1 , Shenqiu Chjan 1 , Qiong Shi 1 , Dun Yang 1,2 , Thaddeus D. Allen 1 *

1 Anticancer Bioscience, Ltd. va J. Maykl Bishop saraton tadqiqot instituti, Chengdu, Xitoy 640000

2 Chengdu an'anaviy xitoy tibbiyot universiteti, 1166 Liutay prospekti, Wenjiang tumani, Chengdu, Xitoy 611137

*Tegishli muallif: Thaddeus D. Allen
Elektron pochta:[email protected]

Qabul qilingan sana: 2020 yil 23 oktyabr Qabul qilingan sana: 2020-yil, 12-noyabr

Iqtibos: Chjan J, Chjan S, Shi Q, Yang D, Allen TD. Poliploid saraton hujayralariga hujum qilish uchun rivojlanayotgan strategiyalar. J Saraton Immunol. 2020 yil 2 (4): 199-206.

Mualliflik huquqi: & nusxa ko'chirish 2020 Zhang J va boshqalar. Bu Creative Commons Attribution License shartlariga muvofiq tarqatiladigan ochiq maqola boʻlib, asl muallif va manba hisoblangan holda har qanday vositada cheksiz foydalanish, tarqatish va koʻpaytirishga ruxsat beradi.

Xulosa

Poliploid saraton hujayralari o'smalarda de novo paydo bo'lishi mumkin yoki ular beixtiyor sitokinetik qobiliyatsizlik tezligini oshiradigan terapevtik vositalar tomonidan qo'zg'atilishi mumkin. Bu hujayralar ko'plab saraton kasalliklarida yomon natija beradi, chunki poliploid saraton hujayralari aneuploid nasl berish uchun xatolikka moyil bo'lgan reduktiv hujayralar bo'linishidan o'tishi mumkin. Immunitet tizimi poliploid saraton hujayralarini aniq tanib olish va olib tashlash mexanizmlarini ishlab chiqdi, ammo ular yomon xulqlilik bilan buzilgan ko'rinadi, shuning uchun poliploid hujayralar terapevtik vositalarga chidamli va metastatik potentsialga ega bo'lgan saraton hujayralari klonlarining rivojlanishiga turtki bo'lishi mumkin. Bu erda biz poliploid saraton hujayralari paydo bo'lishi, immunitet tizimi va poliploid saraton hujayralariga to'g'ridan -to'g'ri hujum qilishi mumkin bo'lgan terapevtik strategiyalar tomonidan tekshiriladigan mexanizmlarni ko'rib chiqamiz.

Kalit so'zlar

Poliploid, mitoz, terapevtik, apoptoz, saraton, immun nazorati

Oddiy poliploid hujayralar

2n xromosomalar bilan to'ldirilgan hujayralar diploid deb ta'riflansa, 2n dan katta hujayralar poliploid deb ataladi. Poliploid hujayralardagi qo'shimcha DNK tarkibi juda xilma-xil bo'lib tuyulishi mumkin, ammo poliploid hujayralar sutemizuvchilarda mavjud bo'lib, ularning rivojlanishida ham, to'qimalarning gomeostazida ham muhim rol o'ynaydi [1]. Plasental sintitiotrofoblastlar, masalan, ona qoni va embrion suyuqligi orasidagi chegarani hosil qiladi. Bu hujayralar gaz va ozuqa almashinuvini ta'minlaydi va homiladorlikni saqlaydigan gormonlar ishlab chiqaradi. Ular ko'p yadroli hujayralar bo'lib, asosiy diploid sitotrofoblast hujayralarining birlashishi natijasida hosil bo'ladi va saqlanadi [2]. Poliploidizatsiya muqobil ravishda genom replikatsiya qilinganda sodir bo'lishi mumkin, ammo hujayralar sitokinezdan o'tmaydi. Bu holat megakaryotsitlarning (MK) pishib etishida yuzaga keladi. Ular diploid, suyak iligi gematopoetik ildiz hujayralaridan rivojlanadi, lekin kamolotga etganda ular endoreplikatsiya, DNKning hujayralar bo'linishisiz replikatsiyasi natijasida poliploidga aylanadi. Bu jarayon trombopoetin gormoni tomonidan boshqariladi va natijada DNK tarkibining 64n gacha bo'lishi mumkin [3]. MKlar uchun yetilishning yakuniy bosqichi yadro tarkibini siqib chiqarishni va ularning sitoplazmasidan proplatelet tuzilmalarini shakllantirishni talab qiladi. Hali ham munozarali bo'lsa -da, MKni ishlab chiqarishda poliploidiyaga bo'lgan talab katta miqdordagi mRNK va oqsilga bo'lgan talab bilan bog'liq bo'lib, ular oxir -oqibat pıhtılaşma va tuzatish uchun trombotsitlarga joylashtiriladi.

Hujayra sintezi natijasida hosil bo'lgan sinsitiotrofoblastlar va endoreplikatsiya orqali MKlar poliploidiya muhim fiziologik rol o'ynaydigan ikkita alohida, maxsus hujayra turini ifodalaydi. Psevdodiploid saraton hujayralarida hujayra bo'linishining normal tekshiruvi va muvozanati buzilganida, anormal poliploid saraton hujayralari ham paydo bo'lishi mumkin. Quyida biz poliploid saraton hujayralari qanday paydo bo'lishini va saraton hujayralari populyatsiyasiga hujum qilishning asosini bayon qilamiz.

Poliploid saraton hujayralari

Saraton kasalligida ro'y beradigan onkogen o'zgarishlar mitotik siljish va sitokinetik etishmovchilikni osonlashtiradi. Bu buzilish xromosomalarning diploid to'plamining bir qismidagi son o'zgarishidagi aneuploidiyani osonlashtiradi. Masalan, BRCA kabi o'simtani bostiruvchilarda funktsiyalarining yo'qolishi2 [4], TP53 [5] va APC [6], barchasi sitokinetik qobiliyatsizlik tezligini oshiradi, kinaz mutatsiyalarini faollashtirish esa mitozning ishonchliligiga ta'sir qilishi mumkin. Signal kaskadlari sentrosomalarning biogenezi va funktsiyasiga, mitotik mil yig'ish punktining (SAC) yaxlitligiga va sitokinezning tugashiga ta'sir qilish uchun yaqinlashadi [7-9]. SAC xromosomalarni aniq ajratish uchun himoya vazifasini bajaradi, kinetoxorlarning mitotik milning mikronaychalariga to'g'ri biriktirilishini va anafazaga o'tishdan oldin ikki yo'naltirilgan opa-singil kinetoxorlar orasidagi optimal kuchlanishni ta'minlaydi (ko'rib chiqish uchun [10-12] ga qarang). Xromosomalarni ajratishdagi nuqsonlar SACni chetlab o'tish natijasida yuzaga keladi deb taxmin qilinadi. Shunday qilib, oldingi onkogen hodisalar anevloidiyani rag'batlantirish orqali keyingi intratumoral genetik heterojenlik uchun debocha bo'lib xizmat qilishi mumkin. Bu vaqt o'tishi bilan saraton hujayralarining yanada agressiv klonlarining paydo bo'lishiga yordam beradi. Yagona hujayrali ketma-ketlik texnologiyalari saraton kasalligida topilgan klonal heterojenlikdagi ulkan chuqurlikni ochib berishda davom etmoqda [13].

Biroq, anevloidiyaga olib keladigan muhim yo'l poliploid qidiruv mahsulotini o'z ichiga olishi mumkin. Poliploidiya aneuploidiyadan farq qiladi. Poliploidiya - bu xromosomalarning faqat bir qismidagi emas, balki sonining o'zgarishi. Saraton hujayralari hayotiy mitozga uchrashi mumkin, lekin keyin sitokinezni tugatolmaydi, natijada ko'p yadroli hujayra hosil bo'ladi. Poliploidiyaning proliferativ tarzda hibsga olingan holat sifatida qarashidan farqli o'laroq, to'plangan ma'lumotlar shuni ko'rsatadiki, poliploid hujayralar xatolarga moyil bo'lishi mumkin bo'lgan reduktiv bo'linishlarga uchrashi mumkin, natijada hayotiy va proliferativ yuqori aneuploid nasl paydo bo'ladi. Diploidiya bilan taqqoslaganda, poliploidiya aneuploidiya uchun chidamli qidiruv vositasi bo'lib xizmat qiladi, chunki DNK tarkibining ko'payishi muhim xromosomalarning yo'qolishini yanada samarali oldini oladi [15].

4n, 8n yoki undan ko'p bo'lgan hujayralar ko'plab o'smalarda mavjud va poliploid hujayralar mavjudligi ko'plab saraton kasalliklarida yomon prognostik ko'rsatkich sifatida tan olinadi [16-18]. Ayniqsa, leykemiya uchun yomon natijani ko'rsatishi uzoq vaqtdan beri tan olingan [19]. Shunday qilib, o'simta hujayralarining poliploidli hovuzi doimiy manba bo'lib xizmat qilishi mumkin, bu erda o'zgaruvchan genomik o'zgarishga ega hujayralar paydo bo'lishi mumkin, ular vaqt o'tishi bilan metastatik potentsiali yaxshilangan terapevtik chidamli hujayralar va hujayralarni ishlab chiqaradi [14,15,20]. 1 -rasm).

Poliploid hujayralar, ayniqsa, urug 'metastatik takrorlanishiga juda mos keladi. Poliploidiyaga javoblardan biri hujayra qarishining rivojlanishidir [21]. Tinchlanuvchi hujayralar sifatida poliploidlar bo'linadigan hujayralarga qaratilgan kimyoterapevtik ta'sirida omon qolishi mumkin. Bundan tashqari, DNKning zararlanishiga javob beradigan genlar poliploid hujayralarda qayta ulanadi, bu esa DNKni tiklash faolligini oshirish uchun bir tarmoqli asosli tuzatish va gomologik bo'lmagan birlashtiruvchi yo'llarni ishga tushiradi. Poliploid hujayralarning keksalikdan hayotga yaroqli aneuploid avlodlar paydo bo'lishi, kemoterapi to'xtatilgandan keyin ham o'smaning qaytalanishiga olib kelishi mumkin. Bir nechta dalillar, ular, aslida, saraton hujayralarining agressiv klonlari paydo bo'lishini va paydo bo'lishini ko'rsatadi [14,20,23,24]. Poliploid saraton hujayralari biologiyasining to'liq tushunilmagan jihatlaridan biri bu poliploidlarda o'ta xavfli saraton bilan bog'liq bo'lgan xususiyatlarning kuchayishi, hatto bu xususiyatlar bog'langan diploid saraton hujayralari havuzida aniq bo'lmasa ham. Masalan, hujayra sikli regulyatorlarining o'zgartirilgan ifodasi [22,25] va epiteliyadan mezenximaga o'tish (EMT) va saraton ildiz hujayralari [26,27] bilan bog'liq markerlar. Poliploid saraton hujayralarida malign xususiyatlarning yaxshilanishining batafsil sharhi nashr etilgan [28].

Muhimi, poliploid saraton hujayralari o'simta hosil qilish qobiliyatiga ega, shuning uchun ular saraton ildiz hujayralariga o'xshash xususiyatlarga ega. Tuxumdon saratoni hujayralaridan ajratilgan poliploid hujayralar tuxumdon saratonining asosiy hujayrali marker CD -sining yuqori darajasini ifodalaydi133, madaniyatda sferoidlarni va immuniteti zaif sichqonlarda o'smalarni hosil qiladi [27]. Ehtimol, bu hujayralarning dedifferentsiatsiya fenotipi bilan bog'liq eng muhimi shundaki, ular yog ', xaftaga va suyakdan mezenximal nasllarning xususiyatlarini olish uchun hujayra madaniyatida tanlab boshqarilishi mumkin [27]. EMTga moyillik uzoq vaqtdan beri metastatik tarqalishni ko'rsatadigan omil hisoblangan, shuning uchun rivojlanish plastisiyasining merosi qiz hujayralar poliploid prekursordan meros bo'lib qolgan muhim xususiyat bo'lishi mumkin.

Bunday meros epigenetik bo'lishi mumkin. Hech bo'lmaganda p53 musbat saraton kasalligida, poliploid hujayralardagi epigenetik o'zgarishlar apoptoz va hujayra tsiklini to'xtatishni faollashtiruvchi p53 transkiption maqsadlarini o'chirishga imkon beradigan dalillar mavjud. Masalan, DNK metilatsiyasining ingibitori 5-aza-2-deoksitsitidin (5-AzadC) p53 maqsadli va siklinga bog'liq kinaz inhibitori p21 CIP1 ning ekspressiyasini tiklaydi, shuningdek poliploid saraton hujayralarining TNF va alfa sezgirligini tiklaydi [22]. Poliploidlarning aneuploid avlodiga epigentik o'zgarishlarni o'tkazish qobiliyati etarlicha o'rganilmagan va bu dori qarshiligi va metastazning paydo bo'lishiga yordam berishi mumkin.

Immun nazorati

Immunitetga ega bo'lgan sichqonlarda poliploid hujayralarni o'tkazishdan keyin paydo bo'ladigan o'smalar asosan psevdodiploid saraton hujayralaridan iborat, shuning uchun ular reduktiv hujayralar bo'linishi naslidan kelib chiqadi [29]. Immun tizimining poliploid hujayralarni aniq aniqlash qobiliyati, bu ploidiyni kamaytirishni talab qiladigan mexanizm bo'lishi mumkin.

Immun tizimining poliploid saraton hujayralarini yo'q qilish mexanizmlari stress signalizatsiyasi orqali paydo bo'ladi. Kalretikulin oqsili polipploid saraton hujayralarining plazma membranasiga qayta joylashadi, u erda fagotsitik hujayralar yuzasida LDL-retseptorlari bilan bog'liq oqsil (LRP) (shuningdek CD91 deb ham ataladi) uchun ligand vazifasini bajaradi. & Ldquoeat me & rdquo signali sifatida harakat qilish uchun transretatsiya endoplazmatik retikulumdan (ER) sodir bo'lishi kerak, bu erda odatda kalretikulin molekulyar shaperon vazifasini bajaradi [31]. Kalretikulinning poliploid hujayrali immunoservillanishining markaziy markazi ekanligi to'g'risida kuchli dalillar poliploid hujayralar hujayra yuzasida kalretikulin ta'sirini ko'rsatuvchi tajribalardan kelib chiqadi, immunitet tanqis sichqonlarda o'simgenezni cheklamaydi, ammo immuniteti buzilmagan sichqonlarda o'simgenezni cheklaydi [29,32]. Poliploid hujayralardagi konstitutsiyaviy ER stressi kalretikulinni hujayra yuzasiga yo'naltiradi, chunki ER stressini engillashtiradigan manipulyatsiyalar, shuningdek, kalretikulinning hujayra yuzasiga tashishini va immunogenlikni kamaytiradi [29].

Poliploid hujayralar, shuningdek, Natural Killer (NK) hujayralari tomonidan kuchaytirilgan immunoservillikka uchraydi. Giperploidiya keltirib chiqaradigan kemoterapevtiklar NKG2D va DNAM-1 hujayralarini faollashtiruvchi NK retseptorlari uchun ligandlarning hujayra yuzasi ifodasini qo'zg'atadi [33]. Shunga qaramay, ER stressiga javob rol o'ynaydi. NKG2D ligand, MICA, HR-116 yo'g'on ichak saratoni hujayralari va K-562 miyelogen leykemiya hujayralari yuzasida ER stressi bilan tartibga solinadi va bu NKlarning sitolitik faolligini qo'zg'atadi [33]. Poliploidiya o'simtaga qarshi immunitetni oshirishi mumkin. Bu doimiy immunoservillashga qaramasdan, saraton tez -tez anevloidiya, tarqalish va immun -efektor hujayralardan saqlanishning tug'ma qobiliyati bilan aniqlanadi. Immunitet nazorat punkti modulyatsiya qiluvchi antikorlarning paydo bo'lishiga qaramay, immun tizimining saraton hujayralarini aniqlash va ularga hujum qilish qobiliyatini tiklash haligacha asosiy klinik muammo hisoblanadi.

Kimyoterapiya bilan bog'liq poliploidiya

Qo'shilgan murakkablik, bo'linadigan hujayralarga hujum qiladigan terapiya beixtiyor poliploidiya rivojlanishini kuchaytirishi mumkinligidan kelib chiqadi. Misol uchun, mitotik milni buzadigan dorilar mitotik falokatdan kelib chiqqan apoptozga olib keladigan uzoq muddat mitotik to'xtashni keltirib chiqaradi. Biroq, vaqti -vaqti bilan hujayralar, ehtimol, apoptoz uchun zarur bo'lgan induktiv signallar ostiga tushib, qochib ketadi. Bu hujayralar muqobil ravishda sitokinezni yakunlay olmay, poliploidga aylanadi. Muvaffaqiyatsiz sitokinez bilan takrorlanadigan takroriy davrlar 4n dan katta ploidli hujayralarga olib kelishi mumkin va apoptotik signalizatsiya nokodazol [34] ta'sirida tetraploid saraton hujayralarida hali ham mavjud bo'lsa-da, tetraploid hujayrali chiziqlar nurlanish va DNK shikastlanishidan o'limga nisbatan ancha chidamli. diploid o'xshashlar [35]. Bu shuni ko'rsatadiki, poliploidizatsiya ichki apoptotik signalizatsiyani faollashtirish qobiliyati pasaygan. Apoptozdan farqli o'laroq, poliploid saraton hujayralarida kuchaytirilgan autofagik oqim kontekstga bog'liq holda ularning uzoq muddatli omon qolishini rag'batlantirishi yoki bostirishi aniqlandi [36,37]. Poliploid saraton hujayralarining barqarorligi, ehtimol, bir nechta qochish mexanizmlarining yaqinlashishi bilan ta'minlangan.

Saraton kasalligining bir nechta sinflari poliploid hujayralar populyatsiyasini qo'zg'atadi, shu jumladan, klinikada qo'llaniladigan taksanlar, masalan, dosetaksel [24,38] va paklitaksel, [39], doksorubitsin [40], nurlanish [14,41] va onkoproteinlar maqsadli birikmalar [7,42]. Bu shuningdek, Aurora kinaz inhibitörleri [37,43] va Polo o'xshash kinaz inhibitörleri [44,45] kabi mitotik mexanizmga to'g'ridan-to'g'ri hujum qiladigan maqsadli kinaz inhibitörlerini ham o'z ichiga oladi. Agar poliploidizatsiya va hujayra bo'linishidan keyin reduktiv hujayralar bo'linishi aneuploidiyaning progressiv rivojlanishiga turtki bo'lsa, poliploid saraton hujayralariga qaratilgan terapevtik ushbu tsiklni qisqartirish, saraton genomining rivojlanishiga hujum qilish va hozirda qo'llanilayotgan ko'pchilikning umumiy samaradorligini oshirish uchun vosita bo'lishi mumkin. davolash usullari.

Poliploid saraton hujayralari rivojlanishining oldini olish

Nazariy jihatdan, diploid saraton hujayralarining poliploid hujayralarga aylanishini kamaytirish evolyutsiyani cheklash strategiyasi bo'lishi mumkin. Bir nechta dalillar ushbu maqsadga erishish uchun kombinatsiyalangan davolash usullarini taklif qiladi. Hech bo'lmaganda madaniyatli diffuzli katta B hujayrali limfoma (DLBCL) hujayra liniyalarida poliploid hujayralar shakllanishiga samarali ta'sir ko'rsatadigan kombinatsiyalangan terapiya - bu histon deatsetilaza kompleksi (HDAC) inhibitori Belinostatni vinka alkaloidi, vinkristin bilan birgalikda qo'llashdir. . Faqat vinkristin, boshqa mil toksinlari singari, mitotik hibsga olish va apoptoz bilan bir qatorda ba'zi polploidiyalarni qo'zg'atishga moyil. Belinostat apoptotik javobni kuchaytiradi. Mualliflarning taxmin qilishicha, poliploid hujayralar kam, chunki hujayralar uzoq vaqt ushlab turiladi, mitotik siljish va sitokinez buziladi [46]. Ko'proq saraton hujayralari o'tkir apoptozga bo'ysunadi. Shunday qilib, bu ikkita dorilarning o'zaro ta'siri hujayralarga tasdiqlangan replikatsiyadan o'tmasdan hujum qiladi.

Keng spektrli siklinga bog'liq kinaz (CDK) inhibitori bo'lgan flavopiridol, shuningdek, mil toksinlari bilan poliploid hujayralar hosil bo'lish moyilligini kamaytiradi [47]. Bu faollik saraton hujayralarining G1 tutilishi bilan bog'liq bo'lib, hatto G1 nazorat punkti javobini bekor qiluvchi va shpindel toksinlari bilan davolashda endoreduplikatsiyaga moyil bo'lgan o'simta bostiruvchi genlar uchun etishmayotgan hujayralarda ham sodir bo'ladi. Shunday qilib, flavopiridolning sitostatik ta'siri, hech bo'lmaganda, shpindel toksinlari natijasida paydo bo'lgan endoruplikatsiya va poliploidiyani inhibe qilishi mumkin. in vitro. Apoptozning flavopiridol induktsiyali G1 tutilishi bilan birga sodir bo'lishi moyilligi CDK inhibitori bilan birgalikda ishlatiladigan hujayra turiga ham, dorilarga ham bog'liq bo'lishi mumkin (ko'rib chiqish uchun [48] ga qarang).

Poliploidiyaning rivojlanishi va saqlanishi energiya sarflanishi mumkin. Poliploid hujayralar hajmi va DNK tarkibini oshirdi va bu DNK sintezining yangi bosqichlarini boshlash bilan birga, diploid hamkasblariga qaraganda ko'proq energiya sarfini talab qiladi. Hujayra energiyasidan foydalanishning asosiy regulyatori sifatida rapamisin kompleksi 1 (mTOR1) ning mexanik maqsadi metabolik va atrof-muhit belgilarini mRNK translatsiyasi va lipid sintezi kabi anabolik jarayonlarni ta'minlaydigan va autofagiya kabi katabolik jarayonlarni cheklashi mumkin bo'lgan voqealar kaskadiga aylantiradi. Aurora kinaz B inhibitörlerinin saratonga qarshi ta'siri mTOR inhibitörleri [49] bilan birgalikda davolash orqali kuchaytiriladi. Rapamitsin ham, torkinib ham (PP242) poliploid o'tkir miyeloid leykemiya (AML) hujayralarida Aurora kinaz inhibitori tomonidan qo'zg'atilgan apoptoz va otofagik o'limni kuchaytirdi. Poliploid hujayralarda glikolitik metabolizm kuchayganligi aniqlandi va bu metabolik stressning kuchayishi bilan bog'liq edi [49]. Xuddi shu yo'nalishda, tabiiy mahsulot resveratrol yoki aspirin faol mahsuloti bo'lgan salitsilat bilan to'g'ridan-to'g'ri yuqori oqim inhibitori mTOR 5 va rsquo AMP bilan faollashtirilgan oqsil kinazining (AMPK) faollashishi polipploid hujayralar shakllanishiga to'sqinlik qilishi mumkin [50]. Bu nokodazol, sitokalazin D yoki Aurora kinaz B inhibitori bilan poliploidni qo'zg'atuvchi dorilar bilan davolash bilan birga sodir bo'ldi. Muhimi, poliploidiyaga qarshi faollik tasdiqlangan in vivo kolorektal saratonning APC min modelidan foydalanish [50].

Mavjud poliploid saraton hujayralariga hujum

Poliploid hujayralarni afzal ko'rish yoki poliploidni aneuploid hujayralarga o'tishini oldini olish o'simta rivojlanishini to'xtatishi mumkin. Poliploid hujayralarni tanlab o'ldiradigan birikmalar uchun yuqori o'tkazuvchanlik skriningi gen dozasi ekspluatatsiya qilinadigan xususiyat bo'lishi mumkinligini ko'rsatadi [51]. Misol uchun, 8-azaguanin, hipoksantin fosforibozil transferaz 1 (HPRT 1) fermenti tomonidan bioaktiv metabolitga aylanishini talab qiladigan birikma poliploid saraton hujayralari uchun ko'proq toksikdir. Qo'shimcha nusxalari HRPT 1 poliploid hujayralarda bu toksiklikning asosi [51]. Boshqa genlarning o'zgartirilgan ifodasi ham ekspluatatsiya qilinishi mumkin. Meyotik hujayralar bo'linishini tartibga soluvchi genlar, poliploid saraton hujayralarida, mitotik bo'linishni tartibga soluvchi genlar bilan bir qatorda regulyatsiya qilinganligi aniqlandi [41,52]. Bu shuni anglatadiki, hujayra bo'linishi, shu jumladan yadro tomurcuklanma, ko'p qutbli bo'linish yoki boshqa usullar yordamida aneuploid naslini chiqaruvchi reduktiv bo'linmalar, diploidlarga qaraganda hujayra bo'linishining alohida oqsillarini ishlatishi mumkin. Poliploid hujayralarda meiozga xos oqsillar mutlaqo zarurmi yoki yo'qmi, noma'lum, ammo bunday zaifliklarni aniqlash poliploid saraton hujayralari uchun maqsadli terapiyaga bir qadam yaqinlashadi.

MYC va Aurora kinaz B ning sintetik o'limini tekshirish uchun hujayra madaniyati tizimi yordamida aniq strategiya aniqlandi. Bcl ning omon qolish a'zolari.2 poliploid hujayralarning turg'unligini ta'minlash uchun oila tasdiqlangan [53,54]. Aurora kinaz B inhibitörleri va pro-omon qolish Bcl inhibitörleri o'rtasidagi hamkorlik2 oqsillar, ilgari o'rganilgan [55-57]. Ichki apoptotik yo'lni faollashtirish orqali apoptozning kuchayishi tufayli kooperativ effektlar qabul qilingan. Biroq, yangi topilmalar alohida mexanizmni taklif qiladi. Pro-omon qolish Bcl2 oila oqsillari ham BH bilan o'zaro ta'sir qiladi3 autofagiyani blokirovka qilish uchun endoplazmatik retikulumda faqat Beclin1 (shuningdek ATG6) proteini [58,59]. Ushbu o'zaro ta'sir poliploidiya bilan birga keladigan o'limga olib keladigan otofagiyaning oldini olish va dorilarga chidamliligiga hissa qo'shish uchun juda muhim ekanligi ko'rsatildi. in vitro model [54]. Ushbu tadqiqot poliploid saraton hujayralariga to'g'ridan -to'g'ri hujum qilishning maqsadli harakat mexanizmini ko'rsatadi. BH3 mimetik preparatlar omon qolish Bcl o'zaro ta'sirini buzadi2 family proteins with the BH3 domain of Beclin1 and this tactic can be used in combination with drugs such as Aurora kinase inhibitors to enhance cell killing. BH3 mimetics have also been shown to be effective alongside other drugs that induce polyploidy [60].

Other means to disrupt the Beclin1/Bcl2 interaction may also prove valuable. Ceramides are a family of lipids composed of sphingosine and a fatty acid chain. They are found in various cellular membrane compartments, including the Golgi and lysosome and can modify cell signaling pathways. Short-chain ceramides have been found to induce the dissociation of the complex formed between Beclin1 and Bcl2 through the activation of c-Jun N-terminal kinase 1 (JNK1) [61]. JNK1 phosphorylates the Bcl2 protein and this interferes with the association between Beclin1 and Bcl2, thereby enabling autophagy [61]. For polyploid cells, this autophagy is lethal. Knockdown of the gene encoding the ceramide transport protein (known as COL4A3BP or CERT), which moves ceramide from the endoplasmic reticulum (ER) to the Golgi apparatus, induces expression of lysosome-associated membrane protein 2 (LAMP2) and increases autophagic flux, leading to polyploid cell death [62]. So, COL4A3BP may be a target for therapeutic intervention to attack polyploid cancer cells that ultimately works via disruption of the Beclin1/ Bcl2 o'zaro ta'sir.

Direct targeting approaches do not only have to target polyploid cells. For example, inhibition of PLK1 alongside treatment with spindle toxins leads to enhanced apoptosis of both diploid and polyploid cancer cells, but polyploid cells have enhanced sensitivity [63]. The enhanced effect of PLK1 inhibition on cells with >4n DNA content was attributed to an inability of polyploid cells to tolerate any further increase in ploidy that was induced by PKL1 inhibisyon. Polyploid cells were more readily moved toward mitotic catastrophe-induced apoptosis. Genome duplication also increases sensitivity to pharmacological inhibitors of mitotic kinesin family member 11 (also known as Eg5) [64] and monopolar spindle protein 1 (MPS1) [65], so sustained inhibition of mitotic regulators is more toxic to polyploid cells than their diploid counterparts. In theory, these approaches will target both diploid and polyploid cancer cells and could be effective therapies for attacking all cancer cells.

Xulosa

Genomic instability is a hallmark of cancer and polyploid cells have emerged as an intermediate cell on the path toward aneuploidy. Approaches that prevent the formation of and/or target existing polyploid cancer cells are actively being investigated. However, we are just beginning to understand how to best attack polyploid cancer cells. It appears combination therapies that attack all cancer cells, but due to unique vulnerabilities can preferential impact polyploid cells, may have promise. Enabling lethal autophagy has emerged as one means to attack the polyploid cell population of cancer. Additional research is also required to investigate the role that polyploid cancer cells could play in anti-tumor immunity. The ER stress response and calreticulin play a role in immune surveillance for aberrant polyploidy, but how this is bypassed to enable the persistence of polyploid cancer cells in patients is enigmatic. Therapeutics that reestablish immune attack on polyploid cells, alongside therapeutics that preferentially attack the vulnerabilities of polyploids, may prove a potent combination that halts tumor progression in its tracks.


Materiallar va uslublar

Turlar

All plants used in this study came from the John Innes Centre seed collection. The species used were the following (the John Innes Centre seed collection accession number is given in parenthesis): Triticum monococcum (1040005), Aegilops squarrosa (2220007), Aegilops speltoides (2140008), Aegilops bicornis (2190001), induced autotetraploid Aegilops bicornis (2200001), Triticum durum (1180351), artificial AADD allotetraploid (Triticum aegilopoides × Aegilops squarrosa, 7010071), Aegilops cilindrica (2100001), Triticum aestivum (1190830), and Aegilops vavilovi (2260001). Ploidy and genome composition of each species is given in Table.

Anther Sections

All spikes were harvested between late April and early September. Spikes at different developmental stages were fixed for 1–2 h in 4% formaldehyde in PEM (50 mM Pipes, 5 mM EGTA, 5 mM MgSO4, pH 6.9). Single spikelets were detached from the spike and sectioned (50–100-μm-thick sections) under water using a Vibratome Series 1000 (TAAB Laboratories Equipment Ltd.). Spikelet sections were placed on multiwell slides (ICN Biomedicals Inc.) coated with 2% (vol/vol) γ-aminopropyl triethoxy silane (APTES Sigma Chemical Co.) and dried overnight at 37°C.

Seeds were germinated and grown for 3–4 d before the root tips were excised, and then fixed in 4% formaldehyde in PEM. The sectioning was carried out in the same way as the anthers.

Fluorescence In Situ Hybridization

Spikelet sections on multiwell slides were dehydrated and rehydrated in a methanol series (30, 50, 70, 100, 70, 50, and 30%) for 5 min each. Sections were treated with 2% (wt/vol) cellulase at 37°C for 1 h. The sections were dehydrated in a series of steps in 70, 90, and 100% ethanol, and air dried. The hybridization mixes with the probes for centromere (CCS1) and telomere (TTTAGGG repeats) were prepared as described in Martinez-Perez et al. 1999. The slides with the hybridization mix were placed in a modified thermocycler (Omnislide Hybaid Ltd.). Denaturation was carried out at 77°C for 10 min, and then hybridization overnight at 37°C. Posthybridization washes were carried out at 42°C with 20% formamide in 0.1× SSC for 10 min.

Probes were labeled with digoxigenin-11-dUTP (Boehringer Mannheim Corp.) and biotin-16-dUTP (Boehringer Mannheim). Probes were detected using FITC-conjugated sheep antidigoxigenin antibody (Boehringer Mannheim) and extravidin-Cy3 (Sigma Chemical Co.). Both antibodies were prepared in 4× SSC, 0.1% Tween 20, and 5% BSA. Antibody incubations were carried out for 1 h in a humid chamber at 37°C. After three washes with 4× SSC and 0.1% Tween 20, slides were counterstained with 4′,6-diamidino-2-phenylindole (DAPI Sigma Chemical Co.), and then mounted in antifade solution (Vectashield Vector Laboratories Inc.).

Microscopy and Imaging Processing

Confocal optical section stacks were collected using a Leica TCS SP confocal microscope (Leica Microsystems, Heidelberg GmbH) equipped with a krypton and an argon laser. All the DAPI confocal images were collected using a confocal microscope (model MRC-1000 Bio-Rad Laboratories) equipped with a UV laser. Low magnification DAPI images (see Fig. 1, a, c, and e) were acquired using a series 300 CCD camera (Photometrics) attached to a Nikon microphot-SA. Images were processed on a Macintosh computer using Adobe Photoshop and printed on a Fuji Pictrography P3000 printer.


13.2 Chromosomal Basis of Inherited Disorders

Ushbu bo'lim oxirida siz quyidagilarni qila olasiz:

  • Describe how a karyogram is created
  • Explain how nondisjunction leads to disorders in chromosome number
  • Compare disorders that aneuploidy causes
  • Describe how errors in chromosome structure occur through inversions and translocations

Inherited disorders can arise when chromosomes behave abnormally during meiosis. We can divide chromosome disorders into two categories: abnormalities in chromosome number and chromosomal structural rearrangements. Because even small chromosome segments can span many genes, chromosomal disorders are characteristically dramatic and often fatal.

Chromosome Identification

Chromosome isolation and microscopic observation forms the basis of cytogenetics and is the primary method by which clinicians detect chromosomal abnormalities in humans. A karyotype is the number and appearance of chromosomes, and includes their length, banding pattern, and centromere position. To obtain a view of an individual’s karyotype, cytologists photograph the chromosomes and then cut and paste each chromosome into a chart, or karyogram . Another name is an ideogram (Figure 13.5).

In a given species, we can identify chromosomes by their number, size, centromere position, and banding pattern. In a human karyotype, autosomes or “body chromosomes” (all of the non–sex chromosomes) are generally organized in approximate order of size from largest (chromosome 1) to smallest (chromosome 22). X va Y xromosomalari avtosomalar emas. However, chromosome 21 is actually shorter than chromosome 22. Researchers discovered this after naming Down syndrome as trisomy 21, reflecting how this disease results from possessing one extra chromosome 21 (three total). Not wanting to change the name of this important disease, scientists retained the numbering of chromosome 21 despite describing it having the shortest set of chromosomes. We may designate the chromosome “arms” projecting from either end of the centromere as short or long, depending on their relative lengths. We abbreviate the short arm p (for “petite”) whereas, we abbreviate the long arm q (because it follows “p” alphabetically). Numbers further subdivide and denote each arm. Using this naming system, we can describe chromosome locations consistently in the scientific literature.

Karyera aloqasi

Genetiklar xromosoma aberatsiyasini aniqlash uchun karyogrammalardan foydalanadilar

Although we refer to Mendel as the “father of modern genetics,” he performed his experiments with none of the tools that the geneticists of today routinely employ. One such powerful cytological technique is karyotyping, a method in which geneticists can identify traits characterized by chromosomal abnormalities from a single cell. To observe an individual’s karyotype, a geneticist first collects a person’s cells (like white blood cells) from a blood sample or other tissue. In the laboratory, he or she stimulates the isolated cells to begin actively dividing. The geneticist then applies the chemical colchicine to cells to arrest condensed chromosomes in metaphase. The geneticist then induces swelling in the cells using a hypotonic solution so the chromosomes spread apart. Finally, the geneticist preserves the sample in a fixative and applies it to a slide.

The geneticist then stains chromosomes with one of several dyes to better visualize each chromosome pair's distinct and reproducible banding patterns. Following staining, the geneticist views the chromosomes using bright-field microscopy. Oddiy dog ​​'tanlovi - Giemsa dog'. Giemsa staining results in approximately 400–800 bands (of tightly coiled DNA and condensed proteins) arranged along all 23 chromosome pairs. An experienced geneticist can identify each band. In addition to the banding patterns, geneticists further identify chromosomes on the basis of size and centromere location. To obtain the classic depiction of the karyotype in which homologous chromosome pairs align in numerical order from longest to shortest, the geneticist obtains a digital image, identifies each chromosome, and manually arranges the chromosomes into this pattern (Figure 13.5).

Eng asosiysi, karyogrammada har bir hujayrada juda ko'p yoki juda kam xromosoma bo'lgan genetik anomaliyalar aniqlanishi mumkin. Examples of this are Down Syndrome, which one identifies by a third copy of chromosome 21, and Turner Syndrome, which is characterized by the presence of only one X chromosome in women instead of the normal two. Geneticists can also identify large DNA deletions or insertions. For instance, geneticists can identify Jacobsen Syndrome—which involves distinctive facial features as well as heart and bleeding defects—by a deletion on chromosome 11. Finally, the karyotype can pinpoint translocations , which occur when a segment of genetic material breaks from one chromosome and reattaches to another chromosome or to a different part of the same chromosome. Translokatsiyalar ma'lum saraton kasalliklarida, shu jumladan surunkali miyelogen leykemiyada uchraydi.

During Mendel’s lifetime, inheritance was an abstract concept that one could only infer by performing crosses and observing the traits that offspring expressed. By observing a karyogram, today’s geneticists can actually visualize an individual's chromosomal composition to confirm or predict genetic abnormalities in offspring, even before birth.

Chromosome Number Disorders

Of all of the chromosomal disorders, chromosome number abnormalities are the most obviously identifiable from a karyogram. Chromosome number disorders include duplicating or losing entire chromosomes, as well as changes in the number of complete sets of chromosomes. They are caused by nondisjunction , which occurs when homologous chromosome pairs or sister chromatids fail to separate during meiosis. Misaligned or incomplete synapsis, or a spindle apparatus dysfunction that facilitates chromosome migration, can cause nondisjunction. The risk of nondisjunction occurring increases with the parents' age.

Nondisjunction can occur during either meiosis I or II, with differing results (Figure 13.6). If homologous chromosomes fail to separate during meiosis I, the result is two gametes that lack that particular chromosome and two gametes with two chromosome copies. If sister chromatids fail to separate during meiosis II, the result is one gamete that lacks that chromosome, two normal gametes with one chromosome copy, and one gamete with two chromosome copies.

Visual Connection

Which of the following statements about nondisjunction is true?

  1. Nondisjunction only results in gametes with n+1 or n–1 chromosomes.
  2. Nondisjunction occurring during meiosis II results in 50 percent normal gametes.
  3. Nondisjunction during meiosis I results in 50 percent normal gametes.
  4. Nondisjunction always results in four different kinds of gametes.

Aneuploidy

Scientists call an individual with the appropriate number of chromosomes for their species euploid . In humans, euploidy corresponds to 22 pairs of autosomes and one pair of sex chromosomes. An individual with an error in chromosome number is described as aneuploid , a term that includes monosomy (losing one chromosome) or trisomy (gaining an extraneous chromosome). Monosomic human zygotes missing any one copy of an autosome invariably fail to develop to birth because they lack essential genes. This underscores the importance of “gene dosage” in humans. Most autosomal trisomies also fail to develop to birth however, duplications of some smaller chromosomes (13, 15, 18, 21, or 22) can result in offspring that survive for several weeks to many years. Trisomik shaxslar boshqa turdagi genetik nomutanosiblikdan aziyat chekadi: gen dozasining oshishi. Individuals with an extra chromosome may synthesize an abundance of the gene products, which that chromosome encodes. This extra dose (150 percent) of specific genes can lead to a number of functional challenges and often precludes development. The most common trisomy among viable births is that of chromosome 21, which corresponds to Down Syndrome. Short stature and stunted digits, facial distinctions that include a broad skull and large tongue, and significant developmental delays characterize individuals with this inherited disorder. We can correlate the incidence of Down syndrome with maternal age. Older women are more likely to become pregnant with fetuses carrying the trisomy 21 genotype (Figure 13.7).

O'rganish uchun havola

Visualize adding a chromosome that leads to Down syndrome in this video simulation.

Polyploidy

We call an individual with more than the correct number of chromosome sets (two for diploid species) polyploid . For instance, fertilizing an abnormal diploid egg with a normal haploid sperm would yield a triploid zygote. Poliploid hayvonlar juda kam uchraydi, yassi chuvalchanglar, qisqichbaqasimonlar, amfibiyalar, baliqlar va kaltakesaklar orasida bir nechta misollar mavjud. Polyploid animals are sterile because meiosis cannot proceed normally and instead produces mostly aneuploid daughter cells that cannot yield viable zygotes. Rarely, polyploid animals can reproduce asexually by haplodiploidy, in which an unfertilized egg divides mitotically to produce offspring. In contrast, polyploidy is very common in the plant kingdom, and polyploid plants tend to be larger and more robust than euploids of their species (Figure 13.8).

Odamlarda jinsiy xromosomalarning ajralmasligi

Odamlar autosomal trisomiyalar va monosomiyalar bilan dramatik zararli ta'sir ko'rsatadi. Shuning uchun, X xromosomasining turli sonlarini tashishga qaramay, erkak urg'ochi va erkaklarning normal ishlashi mumkinligi mantiqiy emasdek tuyulishi mumkin. Rather than a gain or loss of autosomes, variations in the number of sex chromosomes occur with relatively mild effects. In part, this happens because of the molecular process X inactivation . Early in development, when female mammalian embryos consist of just a few thousand cells (relative to trillions in the newborn), one X chromosome in each cell inactivates by tightly condensing into a quiescent (dormant) structure, or a Barr body. The chance that an X chromosome (maternally or paternally derived) inactivates in each cell is random, but once this occurs, all cells derived from that one will have the same inactive X chromosome or Barr body. Bu jarayon orqali ayollar X xromosomasining ikki marta genetik dozasini qoplaydi. In so-called “tortoiseshell” cats, we observe embryonic X inactivation as color variegation (Figure 13.9). Females that are heterozygous for an X-linked coat color gene will express one of two different coat colors over different regions of their body, corresponding to whichever X chromosome inactivates in that region's embryonic cell progenitor.

Anormal miqdordagi X xromosomalari bo'lgan odam har bir hujayradagi bitta X xromosomasidan tashqari hammasini inaktiv qiladi. Shu bilan birga, hatto faol bo'lmagan X xromosomalari ham bir nechta genlarni ifodalashda davom etadi va X xromosomalari ayol tuxumdonlarining to'g'ri pishishi uchun qayta faollashishi kerak. As a result, X-chromosomal abnormalities typically occur with mild mental and physical defects, as well as sterility. Agar X xromosomasi umuman yo'q bo'lsa, bachadonda shaxs rivojlanmaydi.

Scientists have identified and characterized several errors in sex chromosome number. Individuals with three X chromosomes, triplo-X, are phenotypically female but express developmental delays and reduced fertility. Klinefelter sindromining bir turiga to'g'ri keladigan XXY genotipi moyaklari mayda, ko'kraklari kattalashgan va sochlari kamaygan erkaklarga to'g'ri keladi. Klinefelter sindromining yanada murakkab turlari mavjud bo'lib, ularda odam beshta X xromosomaga ega. Barcha turlarda, bittadan tashqari har bir X xromosomasi ortiqcha genetik dozani qoplash uchun inaktivatsiyaga uchraydi. We see this as several Barr bodies in each cell nucleus. X0 genotipi (ya'ni, faqat bitta jinsiy xromosoma) sifatida tavsiflangan Tyorner sindromi fenotipik jihatdan qisqa bo'yli, bo'yin mintaqasida to'rli teri, eshitish va yurak nuqsonlari va bepushtlikka ega bo'lgan ayol kishiga mos keladi.

Ko'paytirish va o'chirish

In addition to losing or gaining an entire chromosome, a chromosomal segment may duplicate or lose itself. Ko'paytirish va o'chirish ko'pincha omon qoladigan, lekin jismoniy va aqliy anormalliklarga ega bo'lgan nasllarni keltirib chiqaradi. Ikki nusxadagi xromosoma segmentlari mavjud xromosomalarga birlashishi yoki yadroda erkin bo'lishi mumkin. Cri-du-chat (from the French for “cry of the cat”) is a syndrome that occurs with nervous system abnormalities and identifiable physical features that result from a deletion of most 5p (the small arm of chromosome 5) (Figure 13.10). Ushbu genotipli chaqaloqlar kasallikning nomi asos bo'lgan baland ovoz bilan yig'laydilar.

Chromosomal Structural Rearrangements

Cytologists have characterized numerous structural rearrangements in chromosomes, but chromosome inversions and translocations are the most common. We can identify both during meiosis by the adaptive pairing of rearranged chromosomes with their former homologs to maintain appropriate gene alignment. If the genes on two homologs are not oriented correctly, a recombination event could result in losing genes from one chromosome and gaining genes on the other. This would produce aneuploid gametes.

Xromosoma inversiyalari

Xromosoma inversiyasi - bu xromosoma qismining ajralib chiqishi, 180° ga aylanishi va qayta kiritilishi. Inversions may occur in nature as a result of mechanical shear, or from transposable elements' action (special DNA sequences capable of facilitating rearranging chromosome segments with the help of enzymes that cut and paste DNA sequences). Unless they disrupt a gene sequence, inversions only change gene orientation and are likely to have more mild effects than aneuploid errors. However, altered gene orientation can result in functional changes because regulators of gene expression could move out of position with respect to their targets, causing aberrant levels of gene products.

An inversion can be pericentric and include the centromere, or paracentric and occur outside the centromere (Figure 13.11). A pericentric inversion that is asymmetric about the centromere can change the chromosome arms' relative lengths, making these inversions easily identifiable.

When one homologous chromosome undergoes an inversion but the other does not, the individual is an inversion heterozygote. Meyoz paytida nuqta-nuqta sinapsini saqlab qolish uchun bir homolog halqa hosil qilishi kerak, ikkinchi homolog esa uning atrofida shakllanishi kerak. Although this topology can ensure that the genes correctly align, it also forces the homologs to stretch and can occur with imprecise synapsis regions (Figure 13.12).

Evolution Connection

The Chromosome 18 Inversion

Not all chromosomes' structural rearrangements produce nonviable, impaired, or infertile individuals. In rare instances, such a change can result in new species evolving. In fact, a pericentric inversion in chromosome 18 appears to have contributed to human evolution. Bu inversiya bizning eng yaqin genetik qarindoshlarimiz - shimpanzalarda mavjud emas. Odamlar va shimpanzelar sitogenetik jihatdan bir nechta xromosomalarda peritsentrik inversiya va odamlardagi ikkinchi xromosomaga mos keladigan shimpanzelarda ikkita alohida xromosomalarning birlashishi bilan farqlanadi.

Scientists believe the pericentric chromosome 18 inversion occurred in early humans following their divergence from a common ancestor with chimpanzees approximately five million years ago. Tadqiqotchilar, bu inversiyani tavsiflab, 19000 ga yaqin nukleotid asoslari 18p da takrorlanganini va takrorlangan mintaqa teskari o'girilib, 18 -chi xromosomaga qayta joylashtirilganligini taxmin qilishdi.

Ushbu inversiya hududida inson va shimpanze genlarini taqqoslash shuni ko'rsatadiki, ikkita gen -ROCK1 va USP14—that are adjacent on chimpanzee chromosome 17 (which corresponds to human chromosome 18) are more distantly positioned on human chromosome 18. This suggests that one of the inversion breakpoints occurred between these two genes. Qizig'i shundaki, odamlar va shimpanzalar ifoda etishadi USP14 kortikal hujayralar va fibroblastlarni o'z ichiga olgan ma'lum hujayralar turlarida alohida darajada. Ehtimol, 18 -chi xromosoma inversiyasi ma'lum bir genlarni qayta joylashtirgan va ularning ifoda darajasini foydali tarzda tiklagan. Chunki ikkalasi ham ROCK1 va USP14 encode cellular enzymes, a change in their expression could alter cellular function. We do not know how this inversion contributed to hominid evolution, but it appears to be a significant factor in the divergence of humans from other primates. 1

Translokatsiyalar

A translocation occurs when a chromosome segment dissociates and reattaches to a different, nonhomologous chromosome. Genlarning joylashuvi tartibga solish ketma-ketligiga nisbatan qanday o'zgarishiga qarab, translokatsiyalar yaxshi yoki halokatli ta'sirga ega bo'lishi mumkin. Notably, specific translocations have occurred with several cancers and with schizophrenia. Reciprocal translocations result from exchanging chromosome segments between two nonhomologous chromosomes such that there is no genetic information gain or loss (Figure 13.13).


Videoni tomosha qiling: Xromosoma, xromatid va xromatin. Hujayra boʻlinishi. Biologiya (Iyul 2022).


Izohlar:

  1. Aza

    What a curious topic

  2. Chinua

    juda zo'r g'oya va o'z vaqtida

  3. Alpha

    Uning aql bovar qilmaydigan qamoqxona ... :)



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