Biology subjects

Mark J. Daly

Publications and source records attributed to Mark J. Daly.

3 recordsLinked to original sources

bioRxiv2016

Estimating the Selective Effect of Heterozygous Protein Truncating Variants from Human Exome Data

The dispensability of individual genes for viability has interested generations of geneticists. For some genes it is essential to maintain two functional chromosomal copies, while other genes may tolerate the loss of one or both copies. Exome sequence data from 60,706 individuals provide sufficient observations of rare protein truncating variants (PTVs) to make genome-wide estimates of selection against heterozygous loss of gene function. The cumulative frequency of rare deleterious PTVs is primarily determined by the balance between incoming mutations and purifying selection rather than genetic drift. This enables the estimation of the genome-wide distribution of selection coefficients for heterozygous PTVs and corresponding Bayesian estimates for individual genes. The strength of selection can help discriminate the severity, age of onset, and mode of inheritance in Mendelian exome sequencing cases. We find that genes under the strongest selection are enriched in embryonic lethal mouse knockouts, putatively cell-essential genes inferred from human tumor cells, Mendelian disease genes, and regulators of transcription. Using an essentiality screen, we find a large set of genes under strong selection that are likely to have critical function but that have not yet been studied extensively.

Genomics↗

bioRxiv2016

Mosaic Mutations in Blood DNA Sequence Are Associated with Solid Tumor Cancers

Recent findings in understanding the causal role of blood-detectable somatic protein-truncating DNA variants in leukemia prompt questions about generalizability of such observations for other cancer types. We used exome sequencing to compare 22 different cancer phenotypes from TCGA data (~8,000 samples) with more than 6,000 controls using a case-control study design and demonstrate that mosaic protein truncating variants in these genes are also associated with solid-tumor cancers. We analyzed tumor DNA samples from TCGA and observed that the cancer-associated mosaic variants are absent from the tumors.\n\nThrough analysis of different cancer phenotypes we observe gene-specificity for mosaic mutations. PPM1D in previous reports has been linked to breast and ovarian cancer, which our analysis confirms as a specifically associated to ovarian cancer. Additionally, glioblastoma, melanoma and lung cancers show gene specific burden of the mosaic protein truncating mutations. Taken together, these results extend existing observations broadly and link solid-tumor cancers to somatic blood DNA changes.

Genetics↗

bioRxiv2016

Rare loss-of-function variants in KMT2F are associated with schizophrenia and developmental disorders

Schizophrenia is a common, debilitating psychiatric disorder with a substantial genetic component. By analysing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls, and 1,077 parent-proband trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants in KMT2F and risk for schizophrenia. In this dataset, we observed three de novo LoF mutations, seven LoF variants in cases, and none in controls (P = 3.3x10-9). To search for LoF variants in KMT2F in individuals without a known neuropsychiatric diagnosis, we examined the exomes of 45,376 individuals in the ExAC database and found only two heterozygous LoF variants, showing that KMT2F is significantly depleted of LoF variants in the general population. Seven of the ten individuals with schizophrenia carrying KMT2F LoF variants also had varying degrees of learning difficulties. We further identified four KMT2F LoF carriers among 4,281 children with diverse, severe, undiagnosed developmental disorders, and two additional carriers in an independent sample of 5,720 Finnish exomes, both with notable neuropsychiatric phenotypes. Together, our observations show that LoF variants in KMT2F cause a range of neurodevelopmental disorders, including schizophrenia. Combined with previous common variant evidence, we more generally implicate epigenetic dysregulation, specifically in the histone H3K4 methylation pathway, as an important mechanism in the pathogenesis of schizophrenia.

Genomics↗