Characterising and predicting haploinsufficiency in the human genome.
Characterising and predicting haploinsufficiency in the human genome.
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DOI：
10.1371/journal.pgen.1001154
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发表时间：
2010-10-14
期刊：
影响因子：
4.5
通讯作者：
Hurles ME
中科院分区：
文献类型：
--
作者：
Huang N;Lee I;Marcotte EM;Hurles ME
单倍不足，其中基因的单个功能拷贝不足以维持正常功能，是显性疾病的主要原因。人类疾病研究已经确定了数百个单倍不足（HI）基因。我们已经编制了一个地图的1,079 haplosufficient（HS）基因的系统识别基因明确和重复损害的拷贝数变异8,458明显健康的个人和对比的基因组，进化，功能和网络属性之间的这些HS基因和已知的HI基因。我们发现HI基因通常比HS基因更长，并且具有更保守的编码序列和启动子。HI基因在早期发育过程中表现出更高的表达水平和更大的组织特异性。此外，在概率人类功能相互作用网络中，HI基因与其他已知HI基因具有更多的相互作用伙伴和更大的网络接近度。我们基于这些差异建立了一个预测模型，并注释了12，443个基因，并预测了它们成为单倍型不足的概率。我们证实了这些预测的单倍不足的表现出单倍不足的预测概率高的基因富集在人类显性疾病的基因和杂合敲除小鼠中引起异常表型的基因。我们已经将这些基于基因的单倍不足预测转化为基因缺失的单倍不足分数，我们证明这比考虑缺失的基因大小或数量更好地区分致病性和良性缺失。这些对单倍不足的强有力预测支持对新型功能丧失变体的临床解释以及对后续研究的变体和基因的优先排序。像大多数复杂的生物一样，人类的基因组中大多数基因都有两个拷贝，一个来自母亲，一个来自父亲。这种冗余为大多数基因提供了备份拷贝，如果一个拷贝因突变而丢失。对于少数基因来说，一个功能拷贝不足以维持正常的人体功能，而导致此类基因其中一个拷贝功能丧失的突变是儿童发育疾病的主要原因。在过去的20年里，医学遗传学家已经确定了300多个这样的基因，但我们不知道我们基因组中的22，000个基因中有多少对基因丢失敏感。通过比较这些已知对基因丢失敏感的近300个基因与超过1,000个单拷贝丢失不会导致疾病的基因，我们已经确定了对单拷贝丢失敏感的基因之间的一些关键进化和功能相似性。我们已经利用这些相似性来预测基因组中大多数基因的单拷贝丢失是否可能导致疾病。这些预测将有助于解释在患者中观察到的突变。
Haploinsufficiency, wherein a single functional copy of a gene is insufficient to maintain normal function, is a major cause of dominant disease. Human disease studies have identified several hundred haploinsufficient (HI) genes. We have compiled a map of 1,079 haplosufficient (HS) genes by systematic identification of genes unambiguously and repeatedly compromised by copy number variation among 8,458 apparently healthy individuals and contrasted the genomic, evolutionary, functional, and network properties between these HS genes and known HI genes. We found that HI genes are typically longer and have more conserved coding sequences and promoters than HS genes. HI genes exhibit higher levels of expression during early development and greater tissue specificity. Moreover, within a probabilistic human functional interaction network HI genes have more interaction partners and greater network proximity to other known HI genes. We built a predictive model on the basis of these differences and annotated 12,443 genes with their predicted probability of being haploinsufficient. We validated these predictions of haploinsufficiency by demonstrating that genes with a high predicted probability of exhibiting haploinsufficiency are enriched among genes implicated in human dominant diseases and among genes causing abnormal phenotypes in heterozygous knockout mice. We have transformed these gene-based haploinsufficiency predictions into haploinsufficiency scores for genic deletions, which we demonstrate to better discriminate between pathogenic and benign deletions than consideration of the deletion size or numbers of genes deleted. These robust predictions of haploinsufficiency support clinical interpretation of novel loss-of-function variants and prioritization of variants and genes for follow-up studies. Humans, like most complex organisms, have two copies of most genes in their genome, one from the mother and one from the father. This redundancy provides a back-up copy for most genes, should one copy be lost through mutation. For a minority of genes, one functional copy is not enough to sustain normal human function, and mutations causing the loss of function of one of the copies of such genes are a major cause of childhood developmental diseases. Over the past 20 years medical geneticists have identified over 300 such genes, but it is not known how many of the 22,000 genes in our genome may also be sensitive to gene loss. By comparing these ∼300 genes known to be sensitive to gene loss with over 1,000 genes where loss of a single copy does not result in disease, we have identified some key evolutionary and functional similarities between genes sensitive to loss of a single copy. We have used these similarities to predict for most genes in the genome, whether loss of a single copy is likely to result in disease. These predictions will help in the interpretation of mutations seen in patients.
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影响因子：
14.9
作者：
Blake JA;Bult CJ;Eppig JT;Kadin JA;Richardson JE;Mouse Genome Database Group
通讯作者：
Mouse Genome Database Group
影响因子：
14.9
作者：
Chatr-aryamontri, Andrew;Ceol, Arnaud;Palazzi, Luisa Montecchi;Nardelli, Giuliano;Schneider, Maria Victoria;Castagnoli, Luisa;Cesareni, Gianni
通讯作者：
Cesareni, Gianni
影响因子：
64.8
作者：
Bustamante, CD;Fledel-Alon, A;Clark, AG
通讯作者：
Clark, AG
Ensembl 2009。
影响因子：
14.9
作者：
Hubbard TJ;Aken BL;Ayling S;Ballester B;Beal K;Bragin E;Brent S;Chen Y;Clapham P;Clarke L;Coates G;Fairley S;Fitzgerald S;Fernandez-Banet J;Gordon L;Graf S;Haider S;Hammond M;Holland R;Howe K;Jenkinson A;Johnson N;Kahari A;Keefe D;Keenan S;Kinsella R;Kokocinski F;Kulesha E;Lawson D;Longden I;Megy K;Meidl P;Overduin B;Parker A;Pritchard B;Rios D;Schuster M;Slater G;Smedley D;Spooner W;Spudich G;Trevanion S;Vilella A;Vogel J;White S;Wilder S;Zadissa A;Birney E;Cunningham F;Curwen V;Durbin R;Fernandez-Suarez XM;Herrero J;Kasprzyk A;Proctor G;Smith J;Searle S;Flicek P
通讯作者：
Flicek P
影响因子：
11.4
作者：
Kondrashov, FA;Koonin, EV
通讯作者：
Koonin, EV