Biology subjects

Taub, M.

Publications and source records attributed to Taub, M..

3 recordsLinked to original sources

bioRxiv2022

Mosaic chromosomal alterations in blood across ancestries via whole-genome sequencing

Mosaic mutations in blood are common with increasing age and are prognostic markers for cancer, cardiovascular dysfunction and other diseases. This group of acquired mutations include megabase-scale mosaic chromosomal alterations (mCAs). These large mutations have mainly been surveyed using SNP array data from individuals of European (EA) or Japanese genetic ancestry. To gain a better understanding of mCA rates and associated risk factors in genetically diverse populations, we surveyed whole genome sequencing data from 67,390 individuals, including 20,132 individuals of African ancestry (AA), and 7,608 of Hispanic ancestry (HA) with deep (30X) whole genome sequencing data from the NHLBI Trans Omics for Precision Medicine (TOPMed) program. We adapted an existing mCA calling algorithm for application to WGS data, and observed higher sensitivity with WGS data, compared with array-based data, in uncovering mCAs at low mutant cell fractions. As in previous reports, we observed a strong association with age and a non-uniform distribution of mCAs across the genome. The presence of autosomal (but not chromosome X) mCAs was associated with an increased risk of both lymphoid and myeloid malignancies. After adjusting for age, we found that individuals of European ancestry have the highest rates of autosomal mCAs, mirroring the higher rate of leukemia in this group. Our analysis also uncovered higher rates of chromosome X mCAs in AA and HA compared to EA, again after adjusting for age. Germline variants in ATM and MPL showed strong associations with mCAs in cis, including ancestry specific variants. And rare variant gene-burden analysis confirmed the association of putatively protein altering variants in ATM and MPL with mCAs in cis. Individual rare variants in DCPS, ADM17, PPP1R16B, and TET2 were all associated with autosomal mCAs and rare variants in OR4C16 were associated with chromosome X mCAs in females. There was significant enrichment of co-occurrence of CHIP mutations and mCAs both altering cancer associated genes TET2, DNMT3A, JAK2, CUX1, and TP53. Overall, our study demonstrates that rates of mCAs differ across populations and that rare inherited germline variants are strongly associated with mCAs across genetically diverse populations. These results strongly motivate further studies of mCAs in under-represented populations to better understand the causes and consequences of this class of somatic variation.

genomics↗

bioRxiv2020

Coding de novo mutations identified by WGS reveal novel orofacial cleft genes

While de novo mutations (DNMs) are known to increase risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human birth defects. Therefore, whole-genome sequencing of 756 case-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions of coding DNMs to OFC risk. Overall, we identified a significant excess of loss-of-function DNMs in genes highly expressed in craniofacial tissues, as well as genes associated with known autosomal dominant OFC syndromes. This analysis also revealed roles for zinc-finger homeobox domain and SOX2-interacting genes in OFC etiology.

genetics↗

bioRxiv2019

Inherited Causes of Clonal Hematopoiesis of Indeterminate Potential in TOPMed Whole Genomes

Age is the dominant risk factor for most chronic human diseases; yet the mechanisms by which aging confers this risk are largely unknown.1 Recently, the age-related acquisition of somatic mutations in regenerating hematopoietic stem cell populations was associated with both hematologic cancer incidence2-4 and coronary heart disease prevalence.5 Somatic mutations with leukemogenic potential may confer selective cellular advantages leading to clonal expansion, a phenomenon termed Clonal Hematopoiesis of Indeterminate Potential (CHIP).6 Simultaneous germline and somatic whole genome sequence analysis now provides the opportunity to identify root causes of CHIP. Here, we analyze high-coverage whole genome sequences from 97,691 participants of diverse ancestries in the NHLBI TOPMed program and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid, and inflammatory traits specific to different CHIP genes. Association of a genome-wide set of germline genetic variants identified three genetic loci associated with CHIP status, including one locus at TET2 that was African ancestry specific. In silico-informed in vitro evaluation of the TET2 germline locus identified a causal variant that disrupts a TET2 distal enhancer. Aggregates of rare germline loss-of-function variants in CHEK2, a DNA damage repair gene, predisposed to CHIP acquisition. Overall, we observe that germline genetic variation altering hematopoietic stem cell function and the fidelity of DNA-damage repair increase the likelihood of somatic mutations leading to CHIP.

genomics↗