Inson genomi - Human genome

Mavzuga texnik bo'lmagan kirish uchun qarang Genetika bilan tanishish.
Genomik ma'lumot
Karyotype.png
Idealizatsiya qilingan odam diploidining grafik tasviri karyotip, genomning xromosomalarga bo'linishini ko'rsatib beradi. Ushbu rasmda 23-xromosoma juftligining ayol (XX) va erkak (XY) versiyalari ko'rsatilgan. Xromosomalar bir tekisda ko'rsatilgan tsentromeralar. Mitokondriyal DNK ko'rsatilmagan.
NCBI genom identifikatori51
Ploidydiploid
Genom hajmi3100 Mb / s[1] haploid genomiga (mega-basepairs) to'g'ri keladi
Jami 6200 Mbp (diploid).
Soni xromosomalar23 juft

The inson genomi to'liq to'plamidir nuklein kislota ketma-ketliklari uchun odamlar sifatida kodlangan DNK 23 ichida xromosoma juftlik hujayra yadrolari va individual tarkibida bo'lgan kichik DNK molekulasida mitoxondriya. Ular odatda yadro genomi sifatida alohida ko'rib chiqiladi va mitoxondriyal genom.[2] Inson genomlar ikkala oqsil kodlovchi DNK genlarini ham o'z ichiga oladi kodlamaydigan DNK. Gaploid tarkibidagi inson genomlari jinsiy hujayralar (the tuxum va sperma jinsiy hujayralar da yaratilgan hujayralar mayoz bosqichi jinsiy ko'payish oldin urug'lantirish yaratadi zigota ) uch milliarddan iborat DNK tayanch juftliklari, esa diploid genomlar ( somatik hujayralar ) DNK tarkibidan ikki baravar ko'p. Odamlar genomlari o'rtasida sezilarli farqlar mavjud (0,1% tartibda tufayli bitta nukleotidli variantlar[3] va ko'rib chiqishda 0,6% indels ),[4] bu odamlar va ularning eng yaqin qarindoshlari o'rtasidagi farqlardan ancha kichikdir bonobos va shimpanze (~1.1% sobit bitta nukleotidli variantlar [5] va indellarni qo'shganda 4%).[6]

Birinchi inson genomlari ketma-ketligi 2001 yil fevral oyida deyarli to'liq qoralama shaklida nashr etilgan Inson genomining loyihasi[7] va Celera korporatsiyasi.[8] Inson genomini loyihalashtirishni ketma-ketlashtirish ishlari yakunlanganligi 2004 yilda genomlar ketma-ketligi nashr etilishi bilan e'lon qilingan bo'lib, ketma-ketlikda atigi 341 bo'shliq qoldirilib, yuqori takrorlanadigan va boshqa DNKni ifodalaydi, o'sha paytda mavjud bo'lgan texnologiya bilan ketma-ketlikni amalga oshirish mumkin emas edi.[9] Inson genomi umurtqali hayvonlar orasida birinchi bo'lib bunday tugallanishga yaqinlashdi va 2018 yilga kelib milliondan ortiq odamlarning diploid genomlari yordamida aniqlandi keyingi avlod ketma-ketligi.[10] Ushbu ma'lumotlar butun dunyo bo'ylab ishlatiladi biotibbiyot fanlari, antropologiya, sud tibbiyoti va boshqa fan sohalari. Bunday genomik tadqiqotlar kasalliklarni tashxislash va davolashda yutuqlarga va ko'plab biologiya sohalarida, shu jumladan yangi tushunchalarga olib keldi inson evolyutsiyasi.

Inson genomining ketma-ketligi (deyarli) to'liq DNK sekvensiyasi bilan aniqlangan bo'lsa-da, u hali to'liq tushunilmagan. Ko'pchilik (ehtimol barchasi ham emas) genlar eksperimental va yuqori samaradorlik kombinatsiyasi bilan aniqlangan bioinformatika yondashuvlar, ammo ularning oqsillari va biologik funktsiyalarini yanada aniqlash uchun hali ko'p ish qilish kerak RNK mahsulotlar. So'nggi natijalar shuni ko'rsatadiki, genom tarkibidagi kodlamaydigan DNKlarning ko'p qismi biokimyoviy faollik, shu jumladan gen ekspressionini tartibga solish, tashkil etish xromosoma me'morchiligi va signallarni boshqarish epigenetik meros.

To'liq genom ketma-ketligini olishdan oldin, inson genlari sonining taxminiy hisob-kitoblari 50,000 dan 140,000 gacha bo'lgan (bu taxminlarga protein bo'lmagan kodlash genlari kiritilganligi to'g'risida vaqti-vaqti bilan noaniqlik bilan).[11] Genomlarning ketma-ketligi sifati va oqsillarni kodlovchi genlarni aniqlash usullari yaxshilanganligi sababli,[9] tan olingan oqsillarni kodlovchi genlar soni 19,000-20,000 gacha tushdi.[12] Biroq, oqsillarni kodlamaydigan, aksincha regulyatorli RNKni ifodalaydigan ketma-ketliklar o'ynaydigan rolni to'liq anglash genlarning umumiy sonini kamida 46,831 ga etkazdi,[13] yana 2300 mikro-RNK geni.[14] 2012 yilga kelib na RNK, na oqsillarni kodlovchi funktsional DNK elementlari qayd etildi.[15] va yaqinda (2018) aholi o'rtasida o'tkazilgan so'rovda inson genomining yana 10% ekvivalenti topildi.[16] Oqsil -kodlash ketma-ketliklari genomning juda oz qismini (taxminan 1,5%) tashkil etadi, qolganlari esa kodlamaydigan RNK genlar, regulyatsion DNK sekanslari, Chiziqlar, Sinuslar, intronlar va hali ketma-ketliklar funktsiya yo'q aniqlandi.[17]

2016 yil iyun oyida olimlar rasmiy ravishda e'lon qilishdi HGP-yozish, inson genomini sintez qilish rejasi.[18][19]

Inson genomlari ketma-ketligining to'liqligi

Asosiy maqola: Inson genomining loyihasi § Tugash holati

2001 yilda inson genomini loyihasini yakunlash to'g'risida e'lon qilingan bo'lsa-da,[17] ketma-ketlikda hali ham yuzlab bo'shliqlar mavjud bo'lib, ular qatorining taxminan 5-10% etishmayapti, asosan heteroxromatik mintaqalar va tsentromeralar va telomerlar, lekin ba'zilari ham evromatik mintaqalar.[20] 2015 yilda yana 50 ta ilgari natijalanmagan mintaqalarni qamrab olgan ketma-ketlik aniqlanganda 160 ta evromatik bo'shliq qoldi.[21] Faqatgina 2020 yilda inson xromosomasining birinchi to'liq telomer-telomer ketma-ketligi aniqlandi, ya'ni X xromosoma.[22]

Molekulyar tashkilot va genlarning tarkibi

Shuningdek qarang: Inson genlarining ro'yxatlari

Odam genomining umumiy uzunligi 3 milliarddan ortiq tayanch juftligini tashkil etadi. Genom 22 juft juft xromosomalarga birlashtirilgan bo'lib, ular termin bilan ataladi autosomalar, ortiqcha 23-juftlik jinsiy xromosomalar (XX) ayolda va (XY) erkakda. Bularning barchasi hujayra yadrosi tarkibidagi katta chiziqli DNK molekulalari. Genom tarkibiga shuningdek kiradi mitoxondrial DNK, har birida mavjud bo'lgan nisbatan kichik dairesel molekula mitoxondriya. A asosidagi ushbu molekulalar va ularning gen tarkibi haqida asosiy ma'lumotlar mos yozuvlar genomi har qanday aniq bir kishining ketma-ketligini anglatmaydigan quyidagi jadvalda keltirilgan. (Ma'lumot manbai: Ensembl genom brauzerining 87-versiyasi[doimiy o'lik havola ], 2016 yilning dekabrida ko'pchilik qadriyatlar uchun; Ensembl genom brauzerining chiqarilishi 68, MiRNA, rRNA, snRNA, snoRNA uchun 2012 yil iyul.)

XromosomaUzunlik
(mm )		Asosiy
juftliklar		O'zgarishlarOqsil-
kodlash
genlar		Pseudo-
genlar		Jami
uzoq
ncRNA		Jami
kichik
ncRNA		miRNArRNKsnRNAsnoRNATurli xil
ncRNA		HavolalarCentromere
pozitsiya
(MB )		Kümülatif
(%)
185248,956,42212,151,14620581220120049613466221145192EBI1257.9
283242,193,52912,945,96513091023103737511540161117176EBI93.316.2
367198,295,55910,638,7151078763711298992913887134EBI9123
465190,214,55510,165,685752727657228922412056104EBI50.429.6
562181,538,2599,519,995876721844235832510661119EBI48.435.8
658170,805,9799,130,4761048801639234812611173105EBI6141.6
754159,345,9738,613,29898988560520890249076143EBI59.947.1
850145,138,6368,221,5206776137352148028865282EBI45.652
948138,394,7176,590,8117866614911906919665196EBI4956.3
1046133,797,4227,223,9447335685792046432875689EBI40.260.9
1146135,086,6227,535,37012988217102336324747697EBI53.765.4
1245133,275,3097,228,1291034617848227722710662115EBI35.870
1339114,364,3285,082,5743273723971044216453475EBI17.973.4
1436107,043,7184,865,9508305235332399210659779EBI17.676.4
1535101,991,1894,515,07661351063925078136313693EBI1979.3
163190,338,3455,101,7028734657991875232535851EBI36.682
172883,257,4414,614,97211975318342356115807199EBI2484.8
182780,373,2854,035,9662702474531093213513641EBI17.287.4
192058,617,6163,858,269147251262817911013293161EBI26.589.3
202164,444,1673,439,6215442493841315715463768EBI27.591.4
211646,709,9832,049,69723418530571165211924EBI13.292.6
221750,818,4682,135,31148832435778315232362EBI14.793.8
X53156,040,8955,753,881842874271258128228564100EBI60.699.1
Y2057,227,415211,6437138871301571738EBI10.4100
mtDNA0.005416,56992913002402000EBIYo'q100
jami3,088,286,401155,630,64520412146001472750371756532194415212213

1-jadval (yuqorida) insonning jismoniy tashkiloti va gen tarkibini umumlashtiradi mos yozuvlar genomi nashr etilganidek, asl tahlilga havolalar bilan Ansambl ma'lumotlar bazasi Evropa bioinformatika instituti (EBI) va Wellcome Trust Sanger instituti. Xromosomalarning uzunligi tayanch juftlari sonini 0,34 nanometrga ko'paytirish orqali aniqlandi, DNK juft spirali. Yangilangan ma'lumotlar asosida inson xromosomalari uzunliklarining yaqinda baholanishi diploid erkak genomi uchun 205,00 sm va ayol uchun 208,23 sm bo'lib, mos ravishda 6,41 va 6,51 pikogramm (pg) vazniga to'g'ri keladi.[23] Oqsillar soni boshlang'ich soniga asoslanadi oldingi mRNK transkriptlar, va mahsulotlarini o'z ichiga olmaydi mRNKgacha muqobil biriktirish, yoki keyin yuzaga keladigan oqsil tuzilishidagi o'zgarishlar tarjima.

Genlarning soni inson genomida to'liq aniq emas, chunki ko'pchilikning vazifasi stenogrammalar noaniqligicha qolmoqda. Bu, ayniqsa, to'g'ri keladi kodlamaydigan RNK (pastga qarang). Oqsillarni kodlovchi genlarning soni yaxshiroq ma'lum, ammo ular funktsional oqsillarni kodlashi mumkin yoki bo'lmasligi mumkin bo'lgan, odatda qisqa muddatlarda kodlangan 1400 ta shubhali genlar qatorida mavjud. ochiq o'qish ramkalari. 2-jadvalda turli xil loyihalar bo'yicha taxminlar keltirilgan va bu nomuvofiqliklar ko'rsatilgan.

Jadval 2. 2018 yil iyul holatiga ko'ra turli xil ma'lumotlar bazalarida inson genlari soni[24]
Gencode[25]Ansambl[26]Refseq[27]SHAHMAT[28]
oqsillarni kodlovchi genlar19,90120,37620,34521,306
lncRNA genlari15,77914,72017,71218,484
antisens RNK5501282694
turli xil RNK2213222213,8994347
Pseudogenes14,723174015,952
umumiy transkriptlar203,835203,903154,484328,827

O'zgarishlar 2016 yil dekabr holatiga ko'ra Ensembl tomonidan tahlil qilingan inson genomlari ketma-ketligida aniqlangan noyob DNK ketma-ketlik farqlari. Belgilangan variatsiyalar soni ortishi kutilmoqda shaxsiy genomlar ketma-ketligi va tahlil qilinganligi. Ushbu jadvalda ko'rsatilgan gen tarkibidan tashqari, inson genomida ko'p miqdordagi ifodalanmagan funktsional ketma-ketliklar aniqlangan (pastga qarang). EBI genom brauzeridagi mos yozuvli xromosoma ketma-ketliklariga oynalarni ochadi.

Kichik kodlamaydigan RNKlar oqsillarni kodlash potentsialiga ega bo'lmagan 200 ga yaqin asoslarning RNKlari. Bunga quyidagilar kiradi: mikroRNKlar yoki miRNA (gen ekspressionining transkripsiyadan keyingi regulyatorlari), kichik yadroli RNKlar, yoki snRNAs (ning RNK tarkibiy qismlari splitseozomalar ) va kichik nukleolyar RNKlar, yoki snoRNA (boshqa RNK molekulalarining kimyoviy modifikatsiyasini boshqarishda ishtirok etadi). Uzoq kodlamaydigan RNKlar oqsillarni kodlash potentsialiga ega bo'lmagan 200 asosdan uzun bo'lgan RNK molekulalari. Bunga quyidagilar kiradi: ribosoma RNKlari, yoki rRNK (ning RNK tarkibiy qismlari ribosomalar ) va boshqa turli xil uzoq RNKlar ishtirok etadi gen ekspressionini tartibga solish, epigenetik DNK nukleotidlarining modifikatsiyalari va histon oqsillar va oqsillarni kodlovchi genlar faoliyatini tartibga solish. Total-small-ncRNA raqamlari va kichik ncNRA'larning ma'lum turlarining raqamlari orasidagi kichik tafovutlar avvalgi qiymatlar Ensembl 87, ikkinchisi Ensembl 68 versiyalari manbalaridan kelib chiqadi.

Axborot tarkibi

Yashil rangdagi har bir xromosomadagi tayanch juftlari sonini ko'rsatadigan diagramma.

The gaploid inson genomi (23 xromosomalar ) taxminan 3 milliard tayanch juftini tashkil etadi va 30000 ga yaqin genni o'z ichiga oladi.[29] Har bir tayanch juftligi 2 bit bilan kodlanishi mumkinligi sababli, bu taxminan 750 ga teng megabayt ma'lumotlar. Shaxsiy somatik (diploid ) hujayra bu miqdorning ikki baravarini, ya'ni taxminan 6 milliard tayanch juftligini o'z ichiga oladi. Erkaklarda ayollarga qaraganda kamroq, chunki Y xromosomasi 57 million asosiy juftni tashkil etadi, X esa taxminan 156 million. Shaxsiy genomlar ketma-ketlikda bir-biridan 1% dan kam farq qilganligi sababli, ma'lum bir odam genomining umumiy ma'lumotnomadagi o'zgarishlari bo'lishi mumkin yo'qotishsiz siqilgan taxminan 4 megabaytgacha.[30]

The entropiya darajasi genomning kodlash va kodlash ketma-ketliklari orasida sezilarli darajada farq qiladi. Kodlash ketma-ketligi uchun har bir tayanch jufti uchun maksimal 2 bitga yaqin (taxminan 45 million tayanch jufti), lekin kodlamaydigan qismlar uchun kamroq. U bitta xromosoma uchun har bir tayanch jufti uchun 1,5 va 1,9 bit oralig'ida, entropiya darajasi har bir juft uchun 0,9 bitdan past bo'lgan Y-xromosomadan tashqari.[31]

Kodlash va DNKni kodlash

Odam genomining tarkibi odatda kodlash va kodlashsiz DNK ketma-ketligiga bo'linadi. DNKni kodlash ko'chirilishi mumkin bo'lgan ketma-ketliklar sifatida aniqlanadi mRNA va tarjima qilingan inson hayoti davomida oqsillarga; bu ketma-ketliklar genomning ozgina qismini egallaydi (<2%). Kodlashsiz DNK oqsillarni kodlash uchun ishlatilmaydigan barcha ketma-ketliklardan (genomning taxminan 98%) iborat.

Ba'zi kodlamaydigan DNKlarda muhim biologik funktsiyalarga ega bo'lgan RNK molekulalari uchun genlar mavjud (kodlashsiz RNK, masalan ribosomal RNK va transfer RNK ). Kodlashsiz DNKning funktsiyasi va evolyutsion kelib chiqishini o'rganish zamonaviy genom tadqiqotlarining muhim maqsadi, shu jumladan KODLASH (DNK elementlari entsiklopediyasi) loyihasi, natijasi molekulyar faollikni ko'rsatadigan turli xil eksperimental vositalardan foydalangan holda, butun inson genomini o'rganishga qaratilgan.

Kodlamaydigan DNK DNKni kodlashdan ancha ustun bo'lganligi sababli, ketma-ket genom tushunchasi DNK-kodlash genining klassik tushunchasiga qaraganda ko'proq yo'naltirilgan analitik tushunchaga aylandi.[32][33]

Kodlash ketma-ketliklari (oqsillarni kodlovchi genlar)

To'liq ro'yxat uchun qarang Odamlarning oqsillarni kodlovchi genlari ro'yxati 1, Odamning oqsillarni kodlovchi genlari ro'yxati 2, Odamlarning oqsillarni kodlovchi genlari ro'yxati 3 va Odamning oqsillarni kodlovchi genlari ro'yxati 4.
Inson genlari transkripsiyalangan oqsillarning funktsiyalari bo'yicha tasniflanadi, ikkala kodlovchi genlar soni va barcha genlarning foizlari sifatida berilgan.[34]

Proteinlarni kodlash ketma-ketliklari inson genomining eng ko'p o'rganilgan va eng yaxshi tushunilgan tarkibiy qismini aks ettiradi. Ushbu ketma-ketliklar oxir-oqibat butun insoniyatning ishlab chiqarishiga olib keladi oqsillar, garchi bir nechta biologik jarayonlar (masalan, DNKni qayta tashkil etish va mRNKgacha muqobil biriktirish ) oqsillarni kodlovchi genlar sonidan ko'ra ko'proq noyob oqsillarni ishlab chiqarishga olib kelishi mumkin. Genomning to'liq modulli oqsillarni kodlash qobiliyati tarkibiga kiradi exome va tomonidan kodlangan DNK sekanslaridan iborat exons bu oqsillarga tarjima qilinishi mumkin. Biologik ahamiyati va genomning 2 foizidan kamrog'ini tashkil etishi sababli ekzomani sekvensiya qilish inson genomi loyihasining birinchi muhim bosqichi edi.

Oqsillarni kodlovchi genlar soni. Kabi ma'lumotlar bazalarida 20000 ga yaqin odam oqsillari izohlangan Uniprot.[35] Tarixiy jihatdan, oqsil genlari bo'yicha hisob-kitoblar juda xilma-xil bo'lib, 1960-yillarning oxirlarida 2.000.000 gacha bo'lgan,[36] Ammo bir necha tadqiqotchilar 1970-yillarning boshlarida taxmin qilingan deb ta'kidladilar mutatsion yuk zararli mutatsiyalardan funktsional lokuslarning umumiy soni uchun taxminan 40 000 yuqori chegara qo'yilgan (bunga protein kodlovchi va funktsional kodlamaydigan genlar kiradi).[37] Odamning oqsillarni kodlovchi genlari soni unchalik murakkab bo'lmagan organizmlarnikidan sezilarli darajada ko'p emas, masalan yumaloq qurt va mevali chivin. Bu farq keng ko'lamli foydalanish natijasida kelib chiqishi mumkin mRNKgacha muqobil biriktirish ekzonlar tanlab qo'shilishi orqali juda ko'p miqdordagi modulli oqsillarni yaratish qobiliyatini ta'minlaydigan odamlarda.

Xromosoma bo'yicha oqsillarni kodlash qobiliyati. Oqsillarni kodlovchi genlar xromosomalar bo'ylab notekis taqsimlanadi, bir necha o'ndan 2000 gacha, ayniqsa yuqori gen zichligi 19, 11 va 1 xromosomalari ichida (1-jadval). Har bir xromosomada turli xil genlarga boy va kambag'al genlar mavjud bo'lib, ular bilan bog'liq bo'lishi mumkin xromosoma polosalari va GK-tarkib.[38] Gen zichligining ushbu tasodifiy naqshlarining ahamiyati yaxshi tushunilmagan.[39]

Oqsillarni kodlovchi genlarning hajmi. Inson genomidagi oqsillarni kodlovchi genlarning hajmi juda katta o'zgaruvchanlikni ko'rsatadi (2-jadval). Oqsillarni kodlovchi genning o'rtacha kattaligi 26,288 bp (o'rtacha = 66,577 bp; jadval 2[40]). Masalan, uchun gen histon H1a (HIST1HIA) nisbatan kichik va sodda, intronlari yo'q va mRNA sekanslarini 781 nt va 215 aminokislota oqsilini (648 nt) kodlaydi. ochiq o'qish doirasi ). Distrofin (DMD) - bu odamning mos yozuvlar genomidagi eng katta oqsil kodlovchi gen bo'lib, umumiy hajmi 2,2 Mb ni tashkil etadi, shu bilan birga Titin (TTN) eng uzun kodlash ketma-ketligiga ega (114,414 bp), eng katta soni exons (363),[41] va eng uzun bitta ekzon (17,106 bp). Butun genom bo'yicha ekzonning o'rtacha kattaligi 122 bp (o'rtacha = 145 bp), ekzonlarning o'rtacha soni 7 (o'rtacha = 8,8), o'rtacha kodlash ketma-ketligi 367 aminokislotani kodlaydi (o'rtacha = 447 aminokislotalar; 21-jadval[17]).

Jadval 1. Odamning oqsillarni kodlovchi genlariga misollar
OqsilXromGenUzunlikExonsExon uzunligiIntron uzunligiAlt qo'shish
Ko'krak bezi saratoniga moyilligi 2-darajali oqsil13BRCA283,7362711,38672,350ha
Kistik fibroz transmembran o'tkazuvchanlik regulyatori7CFTR202,881274,440198,441ha
Sitoxrom bMTMTCYB1,14011,1400yo'q
DistrofinXDMD2,220,3817910,5002,209,881ha
Gliseraldegid-3-fosfat dehidrogenaza12GAPDH4,44491,4253,019ha
Gemoglobin beta birligi11HBB1,6053626979yo'q
Giston H1A6HIST1H1A78117810yo'q
Titin2TTN281,434364104,301177,133ha

Jadval 2. Odamning oqsillarni kodlovchi genlariga misollar. Xrom, xromosoma. Alt qo'shilish, muqobil mRNA qo'shilish. (Ma'lumot manbai: Ensembl genom brauzeri 68-nashr, 2012 yil iyul)

Yaqinda inson genomining yangilangan ma'lumotlarini muntazam ravishda meta-tahlil qilish[40] insonning mos yozuvlar genomidagi eng katta protein-kodlovchi gen ekanligini aniqladi RBFOX1 (RNK bilan bog'lovchi oqsil, tulki-1 gomolog 1), jami 2,47 MB. Butun genom bo'yicha, oqsillarni kodlovchi genlarning tuzilgan to'plamini hisobga olgan holda, ekzonning o'rtacha kattaligi hozirda 133 bp (o'rtacha = 309 bp), ekzonlar o'rtacha soni hozirda 8 (o'rtacha = 11) deb baholanmoqda ) va o'rtacha kodlash ketma-ketligi hozirda 425 aminokislotani (o'rtacha = 553 aminokislotani kodlaydi; 2 va 5-jadvallar[40]).

Kodlamaydigan DNK (ncDNA)

Asosiy maqola: Kodlashsiz DNK

Kodlashsiz DNK genom tarkibidagi barcha DNK ketma-ketliklari deb ta'riflanadi, ular oqsillarni kodlovchi ekzonlar tarkibida mavjud emas va shuning uchun ular hech qachon ifoda etilgan oqsillarning aminokislotalar qatoriga kirmaydi. Ushbu ta'rifga ko'ra, odam genomlarining 98% dan ortig'i ncDNA dan iborat.

Kodlamaydigan DNKning ko'plab sinflari, jumladan kodlanmaydigan RNK (masalan, tRNK va rRNK) uchun genlar, psevdogenlar, intronlar, mRNKning tarjima qilinmagan hududlari, regulyatsion DNK sekanslari, takrorlanadigan DNK sekanslari va mobil genetik elementlar bilan bog'liq ketma-ketliklar aniqlandi.

Genlarga kiritilgan ko'plab ketma-ketliklar, shuningdek, kodlanmagan DNK sifatida aniqlanadi. Bularga kodlamaydigan RNK uchun genlar (masalan, tRNK, rRNK) va oqsil kodlovchi genlarning tarjima qilinmagan tarkibiy qismlari (masalan, intronlar va mRNKning tarjima qilinmagan 5 'va 3' hududlari) kiradi.

Proteinlarni kodlash ketma-ketliklari (xususan, kodlash) exons ) inson genomining 1,5% dan kamini tashkil qiladi.[17] Bundan tashqari, inson genomining taxminan 26% tashkil etadi intronlar.[42] Genlar (ekzonlar va intronlar) va ma'lum tartibga solish sekanslaridan (8-20%) tashqari, inson genomida kodlanmagan DNK mintaqalari mavjud. Hujayra fiziologiyasida rol o'ynaydigan kodlamaydigan DNKning aniq miqdori qizg'in muhokama qilindi. Tomonidan so'nggi tahlillar KODLASH loyiha shuni ko'rsatadiki, butun inson genomining 80% transkripsiyaga uchraydi, tartibga soluvchi oqsillar bilan bog'lanadi yoki boshqa biokimyoviy faollik bilan bog'liq.[15]

Ammo, bu biokimyoviy faollikning barchasi hujayra fiziologiyasiga hissa qo'shadimi yoki uning muhim qismi transkripsiya va biokimyoviy shovqin bo'lib, u organizm tomonidan faol ravishda filtrlanishi kerak.[43] Proteinlarni kodlash ketma-ketliklari, intronlar va tartibga soluvchi mintaqalar bundan mustasno, kodlamaydigan DNKning ko'p qismi quyidagilardan iborat: rol o'ynamaydigan ko'plab DNK sekanslari gen ekspressioni muhim biologik funktsiyalarga ega. Qiyosiy genomika Tadqiqotlar shuni ko'rsatadiki, genomning taxminan 5% yuqori darajadagi kodlanmagan DNK sekanslarini o'z ichiga oladi saqlanib qolgan, ba'zida yuz millionlab yillarni ifodalaydigan vaqt o'lchovlarida bu kodlash mumkin bo'lmagan mintaqalar kuchli ekanligini anglatadi evolyutsion bosim va ijobiy tanlov.[44]

Ushbu ketma-ketliklarning aksariyati xromosomalarning tuzilishini mintaqalarni cheklash orqali tartibga soladi heteroxromatin kabi xromosomalarning tuzilish xususiyatlarini shakllantirish va tartibga solish telomerlar va tsentromeralar. Kodlashtirilmagan boshqa mintaqalar xizmat qiladi DNK replikatsiyasining kelib chiqishi. Nihoyat, bir nechta mintaqalar funktsional kodlanmaydigan RNKga o'tkaziladi, ular oqsillarni kodlovchi genlarning ekspressionini tartibga soladi (masalan,[45] ), mRNA tarjimasi va barqarorligi (qarang miRNA ), xromatin tuzilishi (shu jumladan histon masalan, o'zgartirishlar[46] ), DNK metilatsiyasi (masalan[47] ), DNK rekombinatsiyasi (masalan[48] ) va boshqa kodlamaydigan RNKlarni o'zaro regulyatsiya qilish (masalan, masalan)[49] ). Ehtimol, ko'pgina transkripsiyalangan kodlash bo'lmagan mintaqalar hech qanday rol o'ynamaydi va bu transkripsiya o'ziga xos bo'lmagan mahsulot hisoblanadi. RNK polimeraza faoliyat.[43]

Pseudogenes

Asosiy maqola: Psevdogen

Pseudogenes - ko'pincha hosil bo'lgan oqsil kodlovchi genlarning harakatsiz nusxalari genlarning takrorlanishi, inaktivatsiya qiluvchi mutatsiyalar to'planishi natijasida ishlamay qolgan. 1-jadval odam genomidagi pseudogenlar soni 13000 tartibda ekanligini ko'rsatadi,[50] va ba'zi xromosomalarda funktsional protein kodlovchi genlar soni bilan deyarli bir xil. Genlarni ko'paytirish - bu yangi genetik materialni yaratadigan asosiy mexanizm molekulyar evolyutsiya.

Masalan, hidni qabul qiluvchi genlar oilasi - bu inson genomidagi pseudogenlarning eng yaxshi hujjatlashtirilgan namunalaridan biridir. Ushbu oiladagi genlarning 60 foizidan ko'prog'i odamlarda funktsional bo'lmagan psevdogenlardir. Taqqoslash uchun, sichqonchani hidlash retseptorlari genlari oilasidagi genlarning atigi 20 foizi psevdogenlardir. Tadqiqotlar shuni ko'rsatadiki, bu turga xos xususiyatdir, chunki eng yaqin primatlarning barchasi psödogenlarga mutanosib ravishda kamroq bo'ladi. Ushbu genetik kashfiyot boshqa sutemizuvchilarga nisbatan odamlarda kamroq o'tkir hidni tushuntirishga yordam beradi.[51]

Kodlamaydigan RNK (ncRNA) uchun genlar

Asosiy maqola: Kodlashsiz RNK

Kodlamaydigan RNK molekulalari hujayralarda juda muhim rol o'ynaydi, ayniqsa ko'plab reaktsiyalarda oqsil sintezi va RNKni qayta ishlash. Kodlashsiz RNK kiradi tRNK, ribosomal RNK, mikroRNK, snRNA va boshqa kodlamaydigan RNK genlari, shu jumladan taxminan 60,000 uzun bo'lmagan kodlash RNKlari (lncRNAs).[15][52][53][54] Xabar qilingan lncRNA genlari soni ko'payishda davom etsa-da va inson genomidagi aniq son hali aniqlanmagan bo'lsa-da, ularning ko'plari ishlamaydigan deb ta'kidlanmoqda.[55]

Ko'p ncRNAlar genlarni boshqarishda va ekspressionida muhim elementlardir. Kodlashsiz RNK epigenetikaga, transkripsiyaga, RNK qo'shilishiga va translyatsiya mexanizmiga ham hissa qo'shadi. Genetik regulyatsiya va kasallikdagi RNKning roli o'rganilmagan genomik murakkablikning yangi potentsial darajasini taklif etadi.[56]

MRNKning intronlari va tarjima qilinmagan mintaqalari

Diskret genlar tomonidan kodlangan ncRNA molekulalaridan tashqari, oqsillarni kodlovchi genlarning dastlabki transkripsiyalari odatda keng ko'lamli kodlash ketma-ketliklarini o'z ichiga oladi. intronlar, 5'-tarjima qilinmagan mintaqalar (5'-UTR) va 3'-tarjima qilinmagan mintaqalar (3'-UTR). Odam genomining ko'pgina oqsillarni kodlovchi genlarida intron sekanslarining uzunligi ekzon sekanslarining uzunligidan 10-100 baravar ko'pdir (2-jadval).

Regulyatsion DNK sekanslari

Inson genomining xilma-xilligi bor tartibga soluvchi ketma-ketliklar nazorat qilish uchun juda muhimdir gen ekspressioni. Konservativ hisob-kitoblar shuni ko'rsatadiki, bu ketma-ketliklar genomning 8 foizini tashkil qiladi,[57] ammo ekstrapolyatsiyalar KODLASH loyiha 20 ga beradi[58]-40%[59] genomning genlarni tartibga soluvchi ketma-ketligi. Kodlamaydigan DNKlarning ayrim turlari genetik "kalit" lar bo'lib, ular oqsillarni kodlamaydi, lekin genlar qachon va qaerda ifodalanishini tartibga soladi (deyiladi kuchaytirgichlar ).[60]

Tartibga soluvchi ketma-ketliklar 1960 yillarning oxiridan beri ma'lum bo'lgan.[61] Inson genomidagi tartibga soluvchi ketma-ketliklarning birinchi identifikatsiyasi rekombinant DNK texnologiyasiga asoslangan edi.[62] Keyinchalik genomik sekvensiya paydo bo'lishi bilan ushbu ketma-ketliklarni identifikatsiyalash evolyutsion konservatsiya bilan xulosa qilinishi mumkin. Orasidagi evolyutsion tarmoq primatlar va sichqoncha Masalan, 70-90 million yil oldin sodir bo'lgan.[63] Shunday qilib, aniqlaydigan genlar ketma-ketligini kompyuter bilan taqqoslash saqlanmagan kodlash ketma-ketliklari ularning genlarni tartibga solish kabi vazifalardagi ahamiyatiga ishora bo'ladi.[64]

Boshqa genomlar, misol uchun, tabiatni muhofaza qilishga qaratilgan usullarga yordam berish maqsadida ketma-ketlik qilingan puferfish genom.[65] Biroq, tartibga solish ketma-ketliklari yuqori tezlikda evolyutsiya jarayonida yo'qoladi va qayta rivojlanadi.[66][67][68]

2012 yildan boshlab, harakatlar DNK va tartibga soluvchi oqsillarning o'zaro ta'sirini texnikada topishga yo'naltirildi ChIP-seq yoki DNK tomonidan paketlanmagan bo'shliqlar gistonlar (DNase yuqori sezgir saytlar ), ikkalasi ham tekshirilgan hujayra turida faol tartibga soluvchi ketma-ketliklar mavjudligini bildiradi.[57]

DNKning takrorlanadigan ketma-ketliklari

Qayta takrorlanadigan DNK sekanslari inson genomining taxminan 50% ni tashkil qiladi.[69]

Odam genomining taxminan 8% tandem DNK massivlari yoki tandem takrorlashlari, bir nechta qo'shni nusxalarga ega bo'lgan past murakkablikdagi takroriy ketma-ketliklardan iborat (masalan, "CAGCAGCAG ...").[70] Tandem ketma-ketliklari o'zgaruvchan uzunliklarda bo'lishi mumkin, ikkita nukleotiddan o'nlab nukleotidgacha. Ushbu ketma-ketliklar, hatto yaqin qarindosh shaxslar orasida ham juda o'zgaruvchan va shuning uchun ham foydalaniladi genealogik DNK tekshiruvi va sud-tibbiy DNK tahlili.[71]

O'ndan kam nukleotidlardan iborat takroriy ketma-ketliklar (masalan, dinukleotid takrorlanishi (AC))n) mikrosatellitlar ketma-ketligi deb nomlanadi. Mikrosatellit ketma-ketliklari orasida trinukleotid takrorlanishi alohida ahamiyatga ega, chunki ba'zida ular ichida bo'ladi kodlash mintaqalari oqsillar uchun genlar va genetik kasalliklarga olib kelishi mumkin. Masalan, Xantington kasalligi trinukleotid takrorlanishining (CAG) kengayishidan kelib chiqadi.n ichida Huntingtin inson xromosomasidagi gen. Telomerlar (chiziqli xromosomalarning uchlari) ketma-ketlikning mikrosatellit heksanukleotid takrorlanishi bilan tugaydi (TTAGGG)n.

Uzunroq ketma-ketliklarning tandem takrorlanishi (10-60 nukleotid uzunlikdagi takroriy ketma-ketliklar massivi) deyiladi minisellitlar.

Ko'chma genetik elementlar (transpozonlar) va ularning qoldiqlari

Transposable genetik elementlar, O'zlarining nusxalarini xost genomidagi boshqa joylarda takrorlashi va qo'shishi mumkin bo'lgan DNK ketma-ketliklari inson genomida juda ko'p tarkibiy qism hisoblanadi. Eng ko'p tarqalgan transpozon nasli, Alu, taxminan 50,000 faol nusxalari bor,[72] va intragenik va intergenik mintaqalarga kiritilishi mumkin.[73] Boshqa bir nasl-nasab, LINE-1, genom uchun 100 ga yaqin faol nusxaga ega (ularning soni odamlar orasida o'zgarib turadi).[74] Qadimgi transpozonlarning funktsional bo'lmagan qoldiqlari bilan birgalikda ular umumiy DNKning yarmidan ko'pini tashkil qiladi.[75] Ba'zida "sakrash genlari" deb nomlangan transpozonlar inson genomini haykaltaroshlikda katta rol o'ynagan. Ushbu ketma-ketliklarning ba'zilari endogen retroviruslar, Genomga doimiy ravishda singib ketgan va keyingi avlodlarga o'tadigan virusli sekanslarning DNK nusxalari.

Inson genomidagi mobil elementlarni tasniflash mumkin LTR retrotranspozonlari (Umumiy genomning 8,3%), Sinuslar (Umumiy genomning 13,1%), shu jumladan Alu elementlari, Chiziqlar (Umumiy genomning 20,4%), SVA va II sinf DNK transpozonlari (Umumiy genomning 2,9%).

Odamlarning genomik o'zgarishi

Asosiy maqola: Insonning genetik o'zgarishi

Inson ma'lumotnomasi genomi

Bir xil egizaklar bundan mustasno, barcha odamlar genomik DNK ketma-ketliklarida sezilarli o'zgarishlarni ko'rsatmoqdalar. Inson mos yozuvlar genomi (HRG) standart ketma-ketlik ma'lumotnomasi sifatida ishlatiladi.

Insonning murojaat genomiga oid bir nechta muhim fikrlar mavjud:

  • HRG - bu gaploid ketma-ketlik. Har bir xromosoma bir martadan ifodalanadi.
  • HRG kompozitsion ketma-ketlikdir va har qanday haqiqiy insonga mos kelmaydi.
  • HRG vaqti-vaqti bilan xatolarni, noaniqliklarni va noma'lum "bo'shliqlarni" tuzatish uchun yangilanadi.
  • HRG hech qanday tarzda "ideal" yoki "mukammal" inson shaxsini anglatmaydi. Bu shunchaki taqqoslash maqsadida ishlatiladigan standartlashtirilgan namoyish yoki model.

The Genom ma'lumotnomasi konsortsiumi HRGni yangilash uchun javobgardir. 38-versiyasi 2013 yil dekabr oyida chiqarilgan.[76]

Insonning genetik o'zgarishini o'lchash

Insonning genetik o'zgarishini tadqiq qilishning aksariyati diqqat markazida bo'lgan bitta nukleotidli polimorfizmlar (SNPs), ular xromosoma bo'ylab alohida asoslarda o'rnini bosuvchi moddalardir. Ko'pgina tahlillar shuni ko'rsatadiki, SNPlar o'rtacha 1000 juft juftlikda, o'rtacha evromatik inson genomi, garchi ular bir xil zichlikda yuzaga kelmasa ham. Shu tariqa ommabop bayonotga amal qilinmoqda: «biz hammamiz, qat'i nazar poyga, genetik jihatdan 99,9% bir xil ",[77] garchi bu ko'pchilik genetiklar tomonidan ma'lum darajada malakaga ega bo'lsa. Masalan, hozirda genomning ancha katta qismi ishtirok etgan deb o'ylashadi nusxa ko'chirish raqamining o'zgarishi.[78] Inson genomidagi SNP turlarini kataloglashtirish bo'yicha keng ko'lamli hamkorlikdagi sa'y-harakatlar Xalqaro HapMap loyihasi.

Kichik turlarning genomik joylari va uzunligi takrorlanadigan ketma-ketliklar ning asosi bo'lgan odamdan odamga juda o'zgaruvchan DNK barmoq izlari va DNKning otalikni tekshirishi texnologiyalar. The heteroxromatik Jami bir necha yuz million tayanch jufti bo'lgan inson genomining qismlari, shuningdek, odam populyatsiyasi ichida juda o'zgaruvchan (ular shunchalik takrorlanadiki va shu qadar uzoqki, ularni hozirgi texnologiya bilan aniq tartiblash mumkin emas). Ushbu mintaqalar oz sonli genlarni o'z ichiga oladi va muhimmi yoki yo'qmi noma'lum fenotipik ta'sir takrorlash yoki heteroxromatinning odatdagi o'zgarishi natijasida hosil bo'ladi.

Eng qo'pol genomik mutatsiyalar jinsiy hujayralar jinsiy hujayralar, ehtimol, ko'rinmas embrionlarni keltirib chiqaradi; ammo, odamlarning bir qator kasalliklari keng ko'lamli genomik anormalliklarga bog'liq. Daun sindromi, Tyorner sindromi, va boshqa bir qator kasalliklar kelib chiqadi mos kelmaydigan butun xromosomalarning Saraton hujayralar tez-tez bor aneuploidiya xromosomalar va xromosoma qo'llari, garchi a sabab va oqibat aneuploidiya va saraton o'rtasidagi munosabatlar o'rnatilmagan.

Insonning genomik o'zgarishini xaritalash

Genom ketma-ketligi genomdagi har bir DNK asosining tartibini sanab o'tgan bo'lsa, genom xaritasi diqqatga sazovor joylarni aniqlaydi. Genom xaritasi genomlar ketma-ketligidan kamroq ma'lumotga ega va genom atrofida harakat qilishda yordam beradi.[79][80]

Variatsiya xaritasiga misol bo'lib, tomonidan ishlab chiqilgan HapMap Xalqaro HapMap loyihasi. HapMap - bu haplotip inson genomining xaritasi, "bu odamning DNK ketma-ketligi o'zgaruvchanligining umumiy naqshlarini tavsiflaydi."[81] U genomdagi bitta DNK harflari yoki bazalarini o'z ichiga olgan kichik o'lchamdagi o'zgarishlarning naqshlarini kataloglaydi.

Tadqiqotchilar jurnalda inson genomidagi keng ko'lamli tarkibiy o'zgarishlarning birinchi ketma-ketlik xaritasini e'lon qilishdi Tabiat 2008 yil may oyida.[82][83] Keng miqyosli strukturaviy o'zgarishlar - bu odamlar orasidagi bir necha mingdan bir necha milliongacha bo'lgan DNK asoslarini o'z ichiga olgan genomdagi farqlar; ba'zilari genomlar ketma-ketligining yutuqlari yoki yo'qotilishlari, boshqalari esa ketma-ketlik cho'zilishlarining qayta tartibga solinishi kabi ko'rinadi. Ushbu o'zgarishlarga quyidagilar kiradi nusxalar sonidagi farqlar jismoniy shaxslar ma'lum bir genga, deletsiyalarga, translokatsiyalarga va inversiyalarga ega.

Odam genomidagi SNP chastotasi

Bitta nukleotidli polimorfizmlar (SNP) inson genomida bir hilda sodir bo'lmaydi. Aslida, unda juda xilma-xillik mavjud SNP har bir genga turli xil selektiv bosimlarni aks ettiruvchi genlar orasidagi chastota, shuningdek genom bo'yicha turli xil mutatsiya va rekombinatsiya stavkalari. Biroq, SNP-lar bo'yicha tadqiqotlar kodlash mintaqalariga to'g'ri kelmaydi, ulardan olingan ma'lumotlar genom bo'ylab SNPlarning umumiy tarqalishini aks ettirishi mumkin emas. Shuning uchun SNP konsortsiumi protokol kodlash mintaqalariga moyilligi bo'lmagan SNPlarni aniqlash uchun ishlab chiqilgan va Konsortsiumning 100000 SNPlari odatda inson xromosomalari bo'yicha ketma-ketlikning xilma-xilligini aks ettiradi. The SNP konsortsiumi 2001 yil birinchi choragining oxiriga kelib genom bo'yicha aniqlangan SNP sonini 300 000 ga etkazishga qaratilgan.[84]

22-xromosomaning uzun qo'li bo'ylab TSC SNP taqsimoti (dan https://web.archive.org/web/20130903043223/http://snp.cshl.org/ ). Har bir ustun 1 Mb oraliqni anglatadi; x o'qida taxminiy sitogenetik holat berilgan. SNP zichligining aniq cho'qqilarini va chuqurliklarini ko'rish mumkin, ehtimol ular mutatsiya, rekombinatsiya va selektsiya tezligini aks ettiradi.

O'zgarishlar kodlamaydigan ketma-ketlik va sinonimik o'zgarishlar kodlash ketma-ketligi odatda sinonimik bo'lmagan o'zgarishlarga qaraganda tez-tez uchraydi, bu aminokislota identifikatorini belgilaydigan pozitsiyalarda xilma-xillikni kamaytiradigan ko'proq selektiv bosimni aks ettiradi. O'tish davri o'zgarishi transversiyalarga qaraganda tez-tez uchraydi, chunki CpG dinukleotidlari mutatsiyaning eng yuqori darajasini, ehtimol deaminatsiyaga bog'liq.

Shaxsiy genomlar

Shuningdek qarang: Shaxsiy genomika

Shaxsiy genomlar ketma-ketligi (deyarli) to'liqdir ketma-ketlik tashkil etuvchi kimyoviy asos juftlarining DNK bitta odamning. Kabi genetik xilma-xillik tufayli tibbiy muolajalar turli odamlarga turlicha ta'sir ko'rsatadi bitta nukleotidli polimorfizmlar (SNP), shaxsiy genomlarni tahlil qilish individual genotiplar asosida shaxsiy tibbiy davolanishga olib kelishi mumkin.[85]

Birinchi shaxsiy genom ketma-ketligi aniqlandi Kreyg Venter 2007 yilda. Shaxsiy genomlar DNK namunalarini taqdim etgan ko'ngillilarning shaxsini himoya qilish bo'yicha "Inson genomlari loyihasi" da tartiblashtirilmagan edi. Ushbu ketma-ketlik turli xil populyatsiyadan bo'lgan bir nechta ko'ngillilarning DNKlaridan olingan.[86] Biroq, Venter boshchiligida Celera Genomics genomni ketma-ketlashtirish bo'yicha harakat, kompozitsion namunani sekvensiyalashdan yakka shaxsdan DNKdan foydalanishga o'tish to'g'risida qaror qabul qilindi, keyinchalik Venterning o'zi ekanligi aniqlandi. Shunday qilib, 2000 yilda chiqarilgan Celera inson genomining ketma-ketligi asosan bitta odamga tegishli edi. Dastlabki kompozitsiyadan olingan ma'lumotlarni keyinchalik almashtirish va ikkala to'plamni ifodalovchi diploid ketma-ketlikni aniqlash xromosomalar Dastlab xabar qilingan gaploid ketma-ketlik o'rniga, birinchi shaxsiy genomni chiqarishga imkon berdi.[87] 2008 yil aprel oyida Jeyms Uotson shuningdek yakunlandi. 2009 yilda Stiven Kveyk o'zining "Heliscope" dizayni bo'yicha sekvensordan olingan o'zining genom ketma-ketligini nashr etdi.[88] Boshchiligidagi Stenford jamoasi Euan Eshli Quake genomida amalga oshirilgan inson genomlarini tibbiy talqini uchun asos yaratdi va birinchi marta butun genomga oid tibbiy qarorlarni qabul qildi.[89] Ushbu jamoa G'arb oilasiga yondashuvni yanada kengaytirdi, Illuminaning shaxsiy genomini ketma-ketlashtirish dasturi doirasida ketma-ket birinchi oila.[90] O'shandan beri yuzlab shaxsiy genomlar ketma-ketligi chiqarildi,[91] shu jumladan Desmond Tutu,[92][93] va a Paleo-Eskimo.[94] 2012 yilda 1092 genom orasida ikkita oilaviy triosning barcha genomlari ketma-ketligi ommaga ma'lum bo'ldi.[3] 2013 yil noyabr oyida ispan oilasi to'rtta shaxsiy ekzome ma'lumotlar to'plamini (genomning taxminan 1%) Creative Commons jamoat mulki litsenziyasi.[95][96] The Shaxsiy genom loyihasi (2005 yilda boshlangan) ikkala genom ketma-ketligini va tegishli tibbiy fenotiplarni ommaga ma'lum qiladiganlar qatoriga kiradi.[97][98]

Ayrim genomlarning ketma-ketligi bundan oldin qadrlanmagan genetik murakkablik darajasini yanada oshkor qildi. Shaxsiy genomika nafaqat SNPlarga, balki tarkibiy o'zgarishlarga ham bog'liq bo'lgan inson genomidagi xilma-xillikning muhim darajasini aniqlashga yordam berdi. Biroq, bunday bilimlarni kasalliklarni davolashda va tibbiyot sohasida qo'llash faqat uning boshlanishida.[99] Exome ketma-ketligi genetik kasallikni aniqlashda yordam beradigan vosita sifatida tobora ommalashib bormoqda, chunki ekzome genomik ketma-ketlikning atigi 1 foizini tashkil qiladi, ammo kasalliklarga sezilarli darajada ta'sir etuvchi mutatsiyalarning taxminan 85 foizini tashkil qiladi.[100]

Inson nokautlari

Odamlarda, genlarni nokaut qilish tabiiy ravishda yuzaga keladi heterozigot yoki bir jinsli funktsiyani yo'qotish genlarni nokaut qilish. Ushbu nokautlarni ko'pincha, ayniqsa, ichkarida farqlash qiyin heterojen genetik kelib chiqishi. They are also difficult to find as they occur in low frequencies.

Populations with a high level of parental-relatedness result in a larger number of homozygous gene knockouts as compared to outbred populations.[101]

Populations with high rates of qarindoshlik, such as countries with high rates of first-cousin marriages, display the highest frequencies of homozygous gene knockouts. Such populations include Pakistan, Iceland, and Amish populations. These populations with a high level of parental-relatedness have been subjects of human knock out research which has helped to determine the function of specific genes in humans. By distinguishing specific knockouts, researchers are able to use phenotypic analyses of these individuals to help characterize the gene that has been knocked out.

A pedigree displaying a first-cousin mating (carriers both carrying heterozygous knockouts mating as marked by double line) leading to offspring possessing a homozygous gene knockout.

Knockouts in specific genes can cause genetic diseases, potentially have beneficial effects, or even result in no phenotypic effect at all. However, determining a knockout's phenotypic effect and in humans can be challenging. Challenges to characterizing and clinically interpreting knockouts include difficulty calling of DNA variants, determining disruption of protein function (annotation), and considering the amount of influence mosaicism has on the phenotype.[101]

One major study that investigated human knockouts is the Pakistan Risk of Myocardial Infarction study. It was found that individuals possessing a heterozygous loss-of-function gene knockout for the APOC3 gene had lower triglycerides in the blood after consuming a high fat meal as compared to individuals without the mutation. However, individuals possessing homozygous loss-of-function gene knockouts of the APOC3 gene displayed the lowest level of triglycerides in the blood after the fat load test, as they produce no functional APOC3 protein.[102]

Human genetic disorders

Qo'shimcha ma'lumotlar: Genetika buzilishi

Most aspects of human biology involve both genetic (inherited) and non-genetic (environmental) factors. Some inherited variation influences aspects of our biology that are not medical in nature (height, eye color, ability to taste or smell certain compounds, etc.). Moreover, some genetic disorders only cause disease in combination with the appropriate environmental factors (such as diet). With these caveats, genetic disorders may be described as clinically defined diseases caused by genomic DNA sequence variation. In the most straightforward cases, the disorder can be associated with variation in a single gene. Masalan, kistik fibroz is caused by mutations in the CFTR gene and is the most common recessive disorder in caucasian populations with over 1,300 different mutations known.[103]

Disease-causing mutations in specific genes are usually severe in terms of gene function and are fortunately rare, thus genetic disorders are similarly individually rare. However, since there are many genes that can vary to cause genetic disorders, in aggregate they constitute a significant component of known medical conditions, especially in pediatric medicine. Molecularly characterized genetic disorders are those for which the underlying causal gene has been identified. Currently there are approximately 2,200 such disorders annotated in the OMIM ma'lumotlar bazasi.[103]

Studies of genetic disorders are often performed by means of family-based studies. In some instances, population based approaches are employed, particularly in the case of so-called founder populations such as those in Finland, French-Canada, Utah, Sardinia, etc. Diagnosis and treatment of genetic disorders are usually performed by a genetik -physician trained in clinical/medical genetics. Natijalari Inson genomining loyihasi are likely to provide increased availability of genetik test for gene-related disorders, and eventually improved treatment. Parents can be screened for hereditary conditions and counselled on the consequences, the probability of inheritance, and how to avoid or ameliorate it in their offspring.

There are many different kinds of DNA sequence variation, ranging from complete extra or missing chromosomes down to single nucleotide changes. It is generally presumed that much naturally occurring genetic variation in human populations is phenotypically neutral, i.e., has little or no detectable effect on the physiology of the individual (although there may be fractional differences in fitness defined over evolutionary time frames). Genetic disorders can be caused by any or all known types of sequence variation. To molecularly characterize a new genetic disorder, it is necessary to establish a causal link between a particular genomic sequence variant and the clinical disease under investigation. Such studies constitute the realm of human molecular genetics.

With the advent of the Human Genome and Xalqaro HapMap loyihasi, it has become feasible to explore subtle genetic influences on many common disease conditions such as diabetes, asthma, migraine, schizophrenia, etc. Although some causal links have been made between genomic sequence variants in particular genes and some of these diseases, often with much publicity in the general media, these are usually not considered to be genetic disorders o'z-o'zidan as their causes are complex, involving many different genetic and environmental factors. Thus there may be disagreement in particular cases whether a specific medical condition should be termed a genetic disorder.

Additional genetic disorders of mention are Kallman syndrome va Pfeiffer sindromi (gene FGFR1), Fuchs corneal dystrophy (gene TCF4), Hirschsprung kasalligi (genes RET and FECH), Bardet-Biedl syndrome 1 (genes CCDC28B and BBS1), Bardet-Biedl syndrome 10 (gene BBS10), and facioscapulohumeral muscular dystrophy type 2 (genes D4Z4 and SMCHD1).[104]

Genome sequencing is now able to narrow the genome down to specific locations to more accurately find mutations that will result in a genetic disorder. Copy number variants (CNVs) and single nucleotide variants (SNVs) are also able to be detected at the same time as genome sequencing with newer sequencing procedures available, called Next Generation Sequencing (NGS). This only analyzes a small portion of the genome, around 1-2%. The results of this sequencing can be used for clinical diagnosis of a genetic condition, including Usher sindromi, retinal disease, hearing impairments, diabetes, epilepsy, Leigh disease, hereditary cancers, neuromuscular diseases, primary immunodeficiencies, og'ir birlashgan immunitet tanqisligi (SCID), and diseases of the mitochondria.[105] NGS can also be used to identify carriers of diseases before conception. The diseases that can be detected in this sequencing include Tay-Sachs disease, Bloom syndrome, Gaucher disease, Canavan disease, familial dysautonomia, cystic fibrosis, o'murtqa mushak atrofiyasi va fragile-X syndrome. The Next Genome Sequencing can be narrowed down to specifically look for diseases more prevalent in certain ethnic populations.[106]

The categorized table below provides the prevalence as well as the genes or chromosomes associated with some human genetic disorders.

BuzuqlikTarqalishiChromosome or gene involved
Chromosomal conditions
Daun sindromi1:60021-xromosoma
Klinefelter sindromi1:500–1000 malesAdditional X chromosome
Tyorner sindromi1:2000 femalesLoss of X chromosome
O'roqsimon hujayra anemiyasi1 in 50 births in parts of Africa; rarer elsewhereβ-globin (on chromosome 11)
Bloom syndrome1:48000 Ashkenazi JewsBLM
Saraton
Ko'krak /Tuxumdon saratoni (susceptibility)~5% of cases of these cancer typesBRCA1, BRCA2
FAP (hereditary nonpolyposis coli)1:3500APC
Lynch sindromi5–10% of all cases of bowel cancerMLH1, MSH2, MSH6, PMS2
Fankoni anemiyasi1:130000 birthsMUXLIS
Neurological conditions
Xantington kasalligi1:20000Huntingtin
Altsgeymer kasalligi ‐ early onset1:2500PS1, PS2, APP
Tay-Sachs1:3600 births in Ashkenazi JewsHEXA gene (on chromosome 15)
Canavan disease2.5% Eastern European Jewish ancestryASPA gene (on chromosome 17)
Familial dysautonomia600 known cases worldwide since discoveryIKBKAP gene (on chromosome 9)
Mo'rt X sindromi1.4:10000 in males, 0.9:10000 in femalesFMR1 gene (on X chromosome)
Mukolipidoz IV turi1:90 to 1:100 in Ashkenazi JewsMCOLN1
Boshqa shartlar
Kistik fibroz1:2500CFTR
Duxenne mushak distrofiyasi1:3500 boysDistrofin
Becker muscular dystrophy1.5-6:100000 malesDMD
Beta talassemiya1:100000HBB
Tug'ma buyrak usti hiperplaziyasi1:280 in Native Americans and Yupik Eskimos

1:15000 in American Caucasians

CYP21A2
Glikogenni saqlash kasalligi I turi1:100000 births in AmericaG6PC
Maple siropi siydik kasalligi1:180000 in the U.S.

1:176 in Mennonite/Amish communities

1:250000 in Austria

BCKDHA

BCKDHB

DBT

DLD

Niemann–Pick disease, SMPD1-associated1,200 cases worldwideSMPD1
Usher sindromi1:23000 in the U.S.

1:28000 in Norway

1:12500 in Germany

CDH23

MYO7A

PCDH15

USH1C

USH1G

USH2A

GPR98

DFNB31

CLRN1

Evolyutsiya

Shuningdek qarang: Inson evolyutsiyasi va Chimpanzee Genome Project

Comparative genomics studies of mammalian genomes suggest that approximately 5% of the human genome has been conserved by evolution since the divergence of extant lineages approximately 200 million years ago, containing the vast majority of genes.[107][108] The published shimpanze genome differs from that of the human genome by 1.23% in direct sequence comparisons.[109] Around 20% of this figure is accounted for by variation within each species, leaving only ~1.06% consistent sequence divergence between humans and chimps at shared genes.[110] This nucleotide by nucleotide difference is dwarfed, however, by the portion of each genome that is not shared, including around 6% of functional genes that are unique to either humans or chimps.[111]

In other words, the considerable observable differences between humans and chimps may be due as much or more to genome level variation in the number, function and expression of genes rather than DNA sequence changes in shared genes. Indeed, even within humans, there has been found to be a previously unappreciated amount of copy number variation (CNV) which can make up as much as 5 – 15% of the human genome. In other words, between humans, there could be +/- 500,000,000 base pairs of DNA, some being active genes, others inactivated, or active at different levels. The full significance of this finding remains to be seen. On average, a typical human protein-coding gene differs from its chimpanzee ortholog by only two aminokislota substitutions; nearly one third of human genes have exactly the same protein translation as their chimpanzee orthologs. A major difference between the two genomes is human xromosoma 2, which is equivalent to a fusion product of chimpanzee chromosomes 12 and 13.[112] (later renamed to chromosomes 2A and 2B, respectively).

Humans have undergone an extraordinary loss of olfactory receptor genes during our recent evolution, which explains our relatively crude sense of hid compared to most other mammals. Evolutionary evidence suggests that the emergence of rangni ko'rish in humans and several other primat species has diminished the need for the sense of smell.[113]

In September 2016, scientists reported that, based on human DNA genetic studies, all non-Africans in the world today can be traced to a single population bu exited Africa between 50,000 and 80,000 years ago.[114]

Mitoxondrial DNK

Inson mitoxondrial DNK is of tremendous interest to geneticists, since it undoubtedly plays a role in mitochondrial disease. It also sheds light on human evolution; for example, analysis of variation in the human mitochondrial genome has led to the postulation of a recent common ancestor for all humans on the maternal line of descent (see Mitoxondrial Momo Havo ).

Due to the lack of a system for checking for copying errors,[iqtibos kerak ] mitochondrial DNA (mtDNA) has a more rapid rate of variation than nuclear DNA. This 20-fold[tekshirish kerak ] higher mutation rate allows mtDNA to be used for more accurate tracing of maternal ancestry.[iqtibos kerak ] Studies of mtDNA in populations have allowed ancient migration paths to be traced, such as the migration of Mahalliy amerikaliklar dan Sibir[iqtibos kerak ] yoki Polineziyaliklar from southeastern Osiyo[iqtibos kerak ]. It has also been used to show that there is no trace of Neandertal DNA in the European gene mixture inherited through purely maternal lineage.[115] Due to the restrictive all or none manner of mtDNA inheritance, this result (no trace of Neanderthal mtDNA) would be likely unless there were a large percentage of Neanderthal ancestry, or there was strong positive selection for that mtDNA (for example, going back 5 generations, only 1 of your 32 ancestors contributed to your mtDNA, so if one of these 32 was pure Neanderthal you would expect that ~3% of your autosomal DNA would be of Neanderthal origin, yet you would have a ~97% chance to have no trace of Neanderthal mtDNA).[iqtibos kerak ]

Epigenome

Shuningdek qarang: Epigenetika

Epigenetics describes a variety of features of the human genome that transcend its primary DNA sequence, such as kromatin packaging, histon modifications and DNK metilatsiyasi, and which are important in regulating gene expression, genome replication and other cellular processes. Epigenetic markers strengthen and weaken transcription of certain genes but do not affect the actual sequence of DNA nucleotides. DNA methylation is a major form of epigenetic control over gene expression and one of the most highly studied topics in epigenetics. During development, the human DNA methylation profile experiences dramatic changes. In early germ line cells, the genome has very low methylation levels. These low levels generally describe active genes. As development progresses, parental imprinting tags lead to increased methylation activity.[116][117]

Epigenetic patterns can be identified between tissues within an individual as well as between individuals themselves. Identical genes that have differences only in their epigenetic state are called epialleles. Epialleles can be placed into three categories: those directly determined by an individual's genotype, those influenced by genotype, and those entirely independent of genotype. The epigenome is also influenced significantly by environmental factors. Diet, toxins, and hormones impact the epigenetic state. Studies in dietary manipulation have demonstrated that methyl-deficient diets are associated with hypomethylation of the epigenome. Such studies establish epigenetics as an important interface between the environment and the genome.[118]

Shuningdek qarang

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