ORCID Profile
0000-0003-2243-5948
Current Organisations
Regeneron Pharmaceuticals Inc
,
Wesleyan University
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Publisher: Springer Science and Business Media LLC
Date: 11-12-1994
DOI: 10.1038/NATURE15393
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2015
Publisher: Springer Science and Business Media LLC
Date: 29-08-2017
DOI: 10.1038/S41467-017-00443-5
Abstract: Variants predicted to result in the loss of function of human genes have attracted interest because of their clinical impact and surprising prevalence in healthy in iduals. Here, we present ALoFT (annotation of loss-of-function transcripts), a method to annotate and predict the disease-causing potential of loss-of-function variants. Using data from Mendelian disease-gene discovery projects, we show that ALoFT can distinguish between loss-of-function variants that are deleterious as heterozygotes and those causing disease only in the homozygous state. Investigation of variants discovered in healthy populations suggests that each in idual carries at least two heterozygous premature stop alleles that could potentially lead to disease if present as homozygotes. When applied to de novo putative loss-of-function variants in autism-affected families, ALoFT distinguishes between deleterious variants in patients and benign variants in unaffected siblings. Finally, analysis of somatic variants in cancer exomes shows that putative loss-of-function variants predicted to be deleterious by ALoFT are enriched in known driver genes.
Publisher: Springer Science and Business Media LLC
Date: 18-10-2021
DOI: 10.1038/S41586-021-04103-Z
Abstract: A major goal in human genetics is to use natural variation to understand the phenotypic consequences of altering each protein-coding gene in the genome. Here we used exome sequencing 1 to explore protein-altering variants and their consequences in 454,787 participants in the UK Biobank study 2 . We identified 12 million coding variants, including around 1 million loss-of-function and around 1.8 million deleterious missense variants. When these were tested for association with 3,994 health-related traits, we found 564 genes with trait associations at P ≤ 2.18 × 10 −11 . Rare variant associations were enriched in loci from genome-wide association studies (GWAS), but most (91%) were independent of common variant signals. We discovered several risk-increasing associations with traits related to liver disease, eye disease and cancer, among others, as well as risk-lowering associations for hypertension ( SLC9A3R2 ), diabetes ( MAP3K15 , FAM234A ) and asthma ( SLC27A3 ). Six genes were associated with brain imaging phenotypes, including two involved in neural development ( GBE1 , PLD1 ). Of the signals available and powered for replication in an independent cohort, 81% were confirmed furthermore, association signals were generally consistent across in iduals of European, Asian and African ancestry. We illustrate the ability of exome sequencing to identify gene–trait associations, elucidate gene function and pinpoint effector genes that underlie GWAS signals at scale.
Publisher: Springer Science and Business Media LLC
Date: 31-10-2012
DOI: 10.1038/NATURE11632
Publisher: Springer Science and Business Media LLC
Date: 09-2012
DOI: 10.1038/NATURE11247
Publisher: Cold Spring Harbor Laboratory
Date: 2011
DOI: 10.1101/GAD.1968411
Abstract: The first wave of personal genomes documents how no single in idual genome contains the full complement of functional genes. Here, we describe the extent of variation in gene and pseudogene numbers between in iduals arising from inactivation events such as premature termination or aberrant splicing due to single-nucleotide polymorphisms. This highlights the inadequacy of the current reference sequence and gene set. We present a proposal to define a reference gene set that will remain stable as more in iduals are sequenced. In particular, we recommend that the ancestral allele be used to define the reference sequence from which a core human reference gene annotation set can be derived. In addition, we call for the development of an expanded gene set to include human-specific genes that have arisen recently and are absent from the ancestral set.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 17-02-2012
Abstract: Identifying genes that give rise to diseases is one of the major goals of sequencing human genomes. However, putative loss-of-function genes, which are often some of the first identified targets of genome and exome sequencing, have often turned out to be sequencing errors rather than true genetic variants. In order to identify the true scope of loss-of-function genes within the human genome, MacArthur et al. (p. 823 see the Perspective by Quintana-Murci ) extensively validated the genomes from the 1000 Genomes Project, as well as an additional European in idual, and found that the average person has about 100 true loss-of-function alleles of which approximately 20 have two copies within an in idual. Because many known disease-causing genes were identified in “normal” in iduals, the process of clinical sequencing needs to reassess how to identify likely causative alleles.
Publisher: Cold Spring Harbor Laboratory
Date: 07-02-2017
DOI: 10.1101/106468
Abstract: Variants predicted to result in the loss of function (LoF) of human genes have attracted interest because of their clinical impact and surprising prevalence in healthy in iduals. Here, we present ALoFT (Annotation of Loss-of-Function Transcripts), a method to annotate and predict the disease-causing potential of LoF variants. Using data from Mendelian disease-gene discovery projects, we show that ALoFT can distinguish between LoF variants deleterious as heterozygotes and those causing disease only in the homozygous state. Investigation of variants discovered in healthy populations suggests that each in idual carries at least two heterozygous premature stop alleles that could potentially lead to disease if present as homozygotes. When applied to de novo pLoF variants in autism-affected families, ALoFT distinguishes between deleterious variants in patients and benign variants in unaffected siblings. Finally, analysis of somatic variants in 6,500 cancer exomes shows that pLoF variants predicted to be deleterious by ALoFT are enriched in known driver genes.
No related grants have been discovered for Suganthi Balasubramanian.