10 research outputs found
Identifying the favored mutation in a positive selective sweep.
Most approaches that capture signatures of selective sweeps in population genomics data do not identify the specific mutation favored by selection. We present iSAFE (for "integrated selection of allele favored by evolution"), a method that enables researchers to accurately pinpoint the favored mutation in a large region (∼5 Mbp) by using a statistic derived solely from population genetics signals. iSAFE does not require knowledge of demography, the phenotype under selection, or functional annotations of mutations
Novel insight into the genetic basis of high-altitude pulmonary hypertension in Kyrgyz highlanders
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Analyzing Genetic Adaptation in Action: Identifying the Evolutionary Mechanisms Rescuing Stressed Populations
Genetic adaptation is central to shaping phenotype diversity among populations. If there was not any genetic adaptation, Homo sapiens was not able to migrate out of their original habitat, east of Africa, to colonize the planet. Interestingly, adaptation has enabled us to occupy a wider range of adverse environments such as, arctic, high-altitude, and highly pathogenic (e.g. areas with high rates of transmission of Malaria) regions. Other phenotypes such as skin pigmentation, size of stature, lactose intolerance and several disease susceptibility are directly linked to genetic adaptation.Adaptation also play an important role in global burden of disease and mortality. One every three deaths worldwide is attributed to the evolution of large asexual cell populations. Adaptation provide pathogens to ability to persist to the immune system or exogenous drug to avoid recovery of the host. It also enables them to revive and relapse the disease after obtaining the drug resistance allele, that is the case for Cancer, HIV, Malaria and many other lethal disease. Moreover, some of the ethnic populations also have a significantly lower susceptibility to an specific disease, such as pulmonary hypertension, Malaria, cardiovascular disease, etc.In all the cases, better understanding of mechanisms of adaptation and the genomic targets of the selection can provide actionable information. For instance, the tedious and expensive process of drug discovery can be facilitated by taking into account of disease susceptibility targets. Better therapy drugs can be made by targeting the adapted loci on the pathogen. Finally, mapping the targets of adaptation provides insights into cryptic biological processes.While human biology is the center of attention, model organisms provide convenient, inexpensive, and salable (to populations) framework to test evolutionary hypotheses. This owes to the fact that the molecular mechanisms of evolution are predominantly similar between any living organism. Here in this dissertation, I utilize experimental evolution of \dmel to test multiple evolutionary hypotheses regarding the mechanisms, targets, modes and tempo of adaptation. To answer these questions, I develop genomic time-series models to describe data and find targets of selection. Using the evolutionary models I analyzed an ethnic population to find disease susceptibility genes
Analyzing Genetic Adaptation in Action: Identifying the Evolutionary Mechanisms Rescuing Stressed Populations
Genetic adaptation is central to shaping phenotype diversity among populations. If there was not any genetic adaptation, Homo sapiens was not able to migrate out of their original habitat, east of Africa, to colonize the planet. Interestingly, adaptation has enabled us to occupy a wider range of adverse environments such as, arctic, high-altitude, and highly pathogenic (e.g. areas with high rates of transmission of Malaria) regions. Other phenotypes such as skin pigmentation, size of stature, lactose intolerance and several disease susceptibility are directly linked to genetic adaptation.Adaptation also play an important role in global burden of disease and mortality. One every three deaths worldwide is attributed to the evolution of large asexual cell populations. Adaptation provide pathogens to ability to persist to the immune system or exogenous drug to avoid recovery of the host. It also enables them to revive and relapse the disease after obtaining the drug resistance allele, that is the case for Cancer, HIV, Malaria and many other lethal disease. Moreover, some of the ethnic populations also have a significantly lower susceptibility to an specific disease, such as pulmonary hypertension, Malaria, cardiovascular disease, etc.In all the cases, better understanding of mechanisms of adaptation and the genomic targets of the selection can provide actionable information. For instance, the tedious and expensive process of drug discovery can be facilitated by taking into account of disease susceptibility targets. Better therapy drugs can be made by targeting the adapted loci on the pathogen. Finally, mapping the targets of adaptation provides insights into cryptic biological processes.While human biology is the center of attention, model organisms provide convenient, inexpensive, and salable (to populations) framework to test evolutionary hypotheses. This owes to the fact that the molecular mechanisms of evolution are predominantly similar between any living organism. Here in this dissertation, I utilize experimental evolution of \dmel to test multiple evolutionary hypotheses regarding the mechanisms, targets, modes and tempo of adaptation. To answer these questions, I develop genomic time-series models to describe data and find targets of selection. Using the evolutionary models I analyzed an ethnic population to find disease susceptibility genes
Multiple mechanisms drive genomic adaptation to extreme O<sub>2</sub> levels in Drosophila melanogaster.
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Multiple mechanisms drive genomic adaptation to extreme O2 levels in Drosophila melanogaster.
To detect the genomic mechanisms underlying evolutionary dynamics of adaptation in sexually reproducing organisms, we analyze multigenerational whole genome sequences of Drosophila melanogaster adapting to extreme O2 conditions over an experiment conducted for nearly two decades. We develop methods to analyze time-series genomics data and predict adaptive mechanisms. Here, we report a remarkable level of synchronicity in both hard and soft selective sweeps in replicate populations as well as the arrival of favorable de novo mutations that constitute a few asynchronized sweeps. We additionally make direct experimental observations of rare recombination events that combine multiple alleles on to a single, better-adapted haplotype. Based on the analyses of the genes in genomic intervals, we provide a deeper insight into the mechanisms of genome adaptation that allow complex organisms to survive harsh environments
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Multiple mechanisms drive genomic adaptation to extreme O2 levels in Drosophila melanogaster.
To detect the genomic mechanisms underlying evolutionary dynamics of adaptation in sexually reproducing organisms, we analyze multigenerational whole genome sequences of Drosophila melanogaster adapting to extreme O2 conditions over an experiment conducted for nearly two decades. We develop methods to analyze time-series genomics data and predict adaptive mechanisms. Here, we report a remarkable level of synchronicity in both hard and soft selective sweeps in replicate populations as well as the arrival of favorable de novo mutations that constitute a few asynchronized sweeps. We additionally make direct experimental observations of rare recombination events that combine multiple alleles on to a single, better-adapted haplotype. Based on the analyses of the genes in genomic intervals, we provide a deeper insight into the mechanisms of genome adaptation that allow complex organisms to survive harsh environments
Recommended from our members
Identifying the favored mutation in a positive selective sweep.
Most approaches that capture signatures of selective sweeps in population genomics data do not identify the specific mutation favored by selection. We present iSAFE (for "integrated selection of allele favored by evolution"), a method that enables researchers to accurately pinpoint the favored mutation in a large region (∼5 Mbp) by using a statistic derived solely from population genetics signals. iSAFE does not require knowledge of demography, the phenotype under selection, or functional annotations of mutations
Recommended from our members
Novel insight into the genetic basis of high-altitude pulmonary hypertension in Kyrgyz highlanders
The Central Asian Kyrgyz highland population provides a unique opportunity to address genetic diversity and understand the genetic mechanisms underlying high-altitude pulmonary hypertension (HAPH). Although a significant fraction of the population is unaffected, there are susceptible individuals who display HAPH in the absence of any lung, cardiac or hematologic disease. We report herein the analysis of the whole-genome sequencing of healthy individuals compared with HAPH patients and other controls (total n = 33). Genome scans reveal selection signals in various regions, encompassing multiple genes from the first whole-genome sequences focusing on HAPH. We show here evidence of three candidate genes MTMR4, TMOD3 and VCAM1 that are functionally associated with well-known molecular and pathophysiological processes and which likely lead to HAPH in this population. These processes are (a) dysfunctional BMP signaling, (b) disrupted tissue repair processes and (c) abnormal endothelial cell function. Whole-genome sequence of well-characterized patients and controls and using multiple statistical tools uncovered novel candidate genes that belong to pathways central to the pathogenesis of HAPH. These studies on high-altitude human populations are pertinent to the understanding of sea level diseases involving hypoxia as a main element of their pathophysiology