Mitochondrial DNA variation across 56,434 individuals in gnomAD.
Mitochondrial DNA variation across 56,434 individuals in gnomAD.
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DOI：
10.1101/gr.276013.121
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发表时间：
2022-03
期刊：
影响因子：
7
通讯作者：
Calvo SE
中科院分区：
文献类型：
--
作者：
Laricchia KM;Lake NJ;Watts NA;Shand M;Haessly A;Gauthier L;Benjamin D;Banks E;Soto J;Garimella K;Emery J;Genome Aggregation Database Consortium;Rehm HL;MacArthur DG;Tiao G;Lek M;Mootha VK;Calvo SE
等位基因频率的基因组数据库对于评估未知意义的临床变异非常有帮助;然而，到目前为止，诸如基因组聚合数据库（gnomAD）等数据库一直专注于核DNA，而忽略了线粒体基因组（mtDNA）。在这里，我们提出了一个调用mtDNA变体的管道，解决了三个技术挑战：（1）检测同质和异质变体，分别存在于所有或一部分mtDNA分子中;（2）环状mtDNA基因组;（3）线粒体起源的核序列（NUMT）不一致。我们观察到每个细胞的mtDNA拷贝数在gnomAD队列中变化，并影响NUMT衍生的假阳性变体调用的比例，这可以解释大多数假定的异质性。为了避免假阳性，我们排除了受污染的样本、细胞系和由于mtDNA拷贝数很少而易于NUMT错位的样本。此外，我们报告了异质性≥ 10%的变体。我们将此管道应用于gnomAD v3.1数据库中的56，434个全基因组序列，其中包括欧洲（58%），非洲（25%），拉丁美洲（10%）和亚洲（5%）血统的个体。我们的gnomAD v3.1版本包含10，850个独特mtDNA变异的群体频率，占所有mtDNA碱基的一半以上。重要的是，我们报告的频率在每个核祖先人口和线粒体单倍型组。同质变体占大多数变体调用（98%）和独特变体（85%）。我们观察到1/250的个体携带异质性超过10%的致病性mtDNA变异体。这些mtDNA群体等位基因频率是免费获得的，将有助于诊断解释和研究。
Genomic databases of allele frequency are extremely helpful for evaluating clinical variants of unknown significance; however, until now, databases such as the Genome Aggregation Database (gnomAD) have focused on nuclear DNA and have ignored the mitochondrial genome (mtDNA). Here, we present a pipeline to call mtDNA variants that addresses three technical challenges: (1) detecting homoplasmic and heteroplasmic variants, present, respectively, in all or a fraction of mtDNA molecules; (2) circular mtDNA genome; and (3) misalignment of nuclear sequences of mitochondrial origin (NUMTs). We observed that mtDNA copy number per cell varied across gnomAD cohorts and influenced the fraction of NUMT-derived false-positive variant calls, which can account for the majority of putative heteroplasmies. To avoid false positives, we excluded contaminated samples, cell lines, and samples prone to NUMT misalignment due to few mtDNA copies. Furthermore, we report variants with heteroplasmy ≥10%. We applied this pipeline to 56,434 whole-genome sequences in the gnomAD v3.1 database that includes individuals of European (58%), African (25%), Latino (10%), and Asian (5%) ancestry. Our gnomAD v3.1 release contains population frequencies for 10,850 unique mtDNA variants at more than half of all mtDNA bases. Importantly, we report frequencies within each nuclear ancestral population and mitochondrial haplogroup. Homoplasmic variants account for most variant calls (98%) and unique variants (85%). We observed that 1/250 individuals carry a pathogenic mtDNA variant with heteroplasmy above 10%. These mtDNA population allele frequencies are freely accessible and will aid in diagnostic interpretation and research studies.
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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
7.7
作者：
Ju YS;Alexandrov LB;Gerstung M;Martincorena I;Nik-Zainal S;Ramakrishna M;Davies HR;Papaemmanuil E;Gundem G;Shlien A;Bolli N;Behjati S;Tarpey PS;Nangalia J;Massie CE;Butler AP;Teague JW;Vassiliou GS;Green AR;Du MQ;Unnikrishnan A;Pimanda JE;Teh BT;Munshi N;Greaves M;Vyas P;El-Naggar AK;Santarius T;Collins VP;Grundy R;Taylor JA;Hayes DN;Malkin D;ICGC Breast Cancer Group;ICGC Chronic Myeloid Disorders Group;ICGC Prostate Cancer Group;Foster CS;Warren AY;Whitaker HC;Brewer D;Eeles R;Cooper C;Neal D;Visakorpi T;Isaacs WB;Bova GS;Flanagan AM;Futreal PA;Lynch AG;Chinnery PF;McDermott U;Stratton MR;Campbell PJ
通讯作者：
Campbell PJ
与成年线粒体疾病有关的核和线粒体DNA突变的患病率。
影响因子：
11.2
作者：
Gorman GS;Schaefer AM;Ng Y;Gomez N;Blakely EL;Alston CL;Feeney C;Horvath R;Yu-Wai-Man P;Chinnery PF;Taylor RW;Turnbull DM;McFarland R
通讯作者：
McFarland R
影响因子：
5.8
作者：
Li, Heng
通讯作者：
Li, Heng
影响因子：
64.8
作者：
CANN, RL;STONEKING, M;WILSON, AC
通讯作者：
WILSON, AC