Biology subjects

Harpak, A.

Publications and source records attributed to Harpak, A..

4 recordsLinked to original sources

bioRxiv2018

Reduced signal for polygenic adaptation of height in UK Biobank

Several recent papers have reported strong signals of selection on European polygenic height scores. These analyses used height effect estimates from the GIANT consortium and replication studies. Here, we describe a new analysis based on the the UK Biobank (UKB), a large, independent dataset. We find that the signals of selection using UKB effect-size estimates for height are strongly attenuated or absent. We also provide evidence that previous analyses were confounded by population stratification Therefore, the conclusion of strong polygenic adaptation now lacks support. Moreover, these discrepancies highlight (1) that methods for correcting for population stratification in GWAS may not always be sufficient for polygenic trait analyses, and (2) that claims of differences in polygenic scores between populations should be treated with caution until these issues are better understood.

evolutionary biology↗

bioRxiv2018

Measurement of selective constraint on human gene expression

Gene expression variation is a major contributor to phenotypic variation in human complex traits. Selection on complex traits may therefore be reflected in constraint on gene expression levels. Here, we explore the effects of stabilizing selection on cis-regulatory genetic variation in humans. We analyze patterns of expression variation at copy number variants and find evidence for selection against large increases in gene expression. Using allele-specific expression (ASE) data, we further show evidence of selection against smaller-effect variants. We estimate that, across all genes, singletons in a sample of 122 individuals have approximately 2.5 x greater effects on expression variance than common variants. Despite their increased effect sizes relative to common variants, we estimate that singletons in the sample studied explain, on average, only 5% of the heritability of gene expression from cis-regulatory variants. Finally, we show that genes depleted for loss-of-function variants are also depleted for cis-eQTLs and have low levels of allelic imbalance, confirming tighter constraint on the expression levels of these genes. We conclude that constraint on gene expression is present, but has relatively weak effects on most cis-regulatory variants, thus permitting high levels of gene-regulatory genetic variation.

genomics↗

bioRxiv2017

Frequent Non-Allelic Gene Conversion On The Human Lineage And Its Effect On The Divergence Of Gene Duplicates

Gene conversion is the copying of genetic sequence from a \"donor\" region to an \"acceptor\". In non-allelic gene conversion (NAGC), the donor and the acceptor are at distinct genetic loci. Despite the role NAGC plays in various genetic diseases and the concerted evolution of gene families, the parameters that govern NAGC are not well-characterized. Here, we survey duplicate gene families and identify converted tracts in 46% of them. These conversions reflect a large GC-bias of NAGC. We develop a sequence evolution model that leverages substantially more information in duplicate sequences than used by previous methods and use it to estimate the parameters that govern NAGC in humans: a mean converted tract length of 250bp and a probability of 2.5x10-7 per generation for a nucleotide to be converted (an order of magnitude higher than the point mutation rate). Despite this high baseline rate, we show that NAGC slows down as duplicate sequences diverge--until an eventual \"escape\" of the sequences from its influence. As a result, NAGC has a small average effect on the sequence divergence of duplicates. This work improves our understanding of the NAGC mechanism and the role that it plays in the evolution of gene duplicates.

genomics↗

bioRxiv2016

Finite-sites multiple mutations interference gives rise to wavelet-like oscillations of multilocus linkage disequilibrium

Within-host adaptation of pathogens such as human immunodeficiency virus (HIV) often occurs at more than two loci. Multiple beneficial mutations may arise simultaneously on different genetic backgrounds and interfere, affecting each other's fixation trajectories. Here, we explore how these adaptive dynamics are mirrored in multilocus linkage disequilibrium (MLD), a measure of multi-way associations between alleles. In the parameter regime corresponding to HIV, we show that deterministic early infection models induce MLD to oscillate over time in a wavelet-like fashion. We find that the frequency of these oscillations is proportional to the rate of adaptation. This signature is robust to drift, but can be eroded by high variation in fitness effects of beneficial mutations. Our findings suggest that MLD oscillations could be used as a signature of interference among multiple equally advantageous mutations and may aid the interpretation of MLD in data.

genetics↗