Biomedical subjects

Andrew D Kern

Publications and source records attributed to Andrew D Kern.

14 recordsLinked to original sources

PubMed2025

Accessible, realistic genome simulation with selection using stdpopsim.

Selection is a fundamental evolutionary force that shapes patterns of genetic variation across species. However, simulations incorporating realistic selection along heterogeneous genomes in complex demographic histories are challenging, limiting our ability to benchmark statistical methods aimed at detecting selection and to explore theoretical predictions. stdpopsim is a community-maintained simulation library that already provides an extensive catalog of species-specific population genetic models. Here we present a major extension to the stdpopsim framework that enables simulation of various modes of selection, including background selection, selective sweeps, and arbitrary distributions of fitness effects (DFE) acting on annotated subsets of the genome (for instance, exons). This extension maintains stdpopsim's core principles of reproducibility and accessibility while adding support for species-specific genomic annotations and published DFE estimates. We demonstrate the utility of this framework by comparing methods for demographic inference, DFE estimation, and selective sweep detection across several species and scenarios. Our results demonstrate the robustness of demographic inference methods to selection on linked sites, reveal the sensitivity of DFE-inference methods to model assumptions, and show how genomic features, like recombination rate and functional sequence density, influence power to detect selective sweeps. This extension to stdpopsim provides a powerful new resource for the population genetics community to explore the interplay between selection and other evolutionary forces in a reproducible, user-friendly framework.

Journal Article↗

PubMed2025

Sweeps in Space: Leveraging Geographic Data to Identify Beneficial Alleles in Anopheles gambiae.

As organisms adapt to environmental changes, natural selection modifies the frequency of nonneutral alleles. For beneficial mutations, the outcome of this process may be a selective sweep, in which an allele rapidly increases in frequency and perhaps reaches fixation within a population. Selective sweeps have well-studied effects on patterns of local genetic variation in panmictic populations, but much less is known about the dynamics of sweeps in continuous space. In particular, because limited movement across a landscape leads to unique patterns of population structure, spatial dynamics may influence the trajectory of selected mutations. Here, we use forward-in-time, individual-based simulations in continuous space to study the impact of space on beneficial mutations as they sweep through a population. In particular, we show that selection changes the joint distribution of allele frequency and geographic range occupied by a focal allele and demonstrate that this signal can be used to identify selective sweeps. We then leverage this signal to identify in-progress selective sweeps within the malaria vector Anopheles gambiae, a species under strong selection pressure from vector control measures. By considering space, we identify multiple previously undescribed variants with potential phenotypic consequences, including mutations impacting known IR-associated genes and altering protein structure and properties. Our results demonstrate a novel signal for detecting selection in spatial population genetic data that may have implications for genomic surveillance and understanding geographic patterns of genetic variation.

Animals↗

PubMed2025

Sweeps in space: leveraging geographic data to identify beneficial alleles in Anopheles gambiae.

As organisms adapt to environmental changes, natural selection modifies the frequency of non-neutral alleles. For beneficial mutations, the outcome of this process may be a selective sweep, in which an allele rapidly increases in frequency and perhaps reaches fixation within a population. Selective sweeps have well-studied effects on patterns of local genetic variation in panmictic populations, but much less is known about the dynamics of sweeps in continuous space. In particular, because limited movement across a landscape leads to unique patterns of population structure, spatial dynamics may influence the trajectory of selected mutations. Here, we use forward-in-time, individual-based simulations in continuous space to study the impact of space on beneficial mutations as they sweep through a population. In particular, we show that selection changes the joint distribution of allele frequency and geographic range occupied by a focal allele and demonstrate that this signal can be used to identify selective sweeps. We then leverage this signal to identify in-progress selective sweeps within the malaria vector Anopheles gambiae , a species under strong selection pressure from vector control measures. By considering space, we identify multiple previously undescribed variants with potential phenotypic consequences, including mutations impacting known IR-associated genes and altering protein structure and properties. Our results demonstrate a novel signal for detecting selection in spatial population genetic data that may have implications for genomic surveillance and understanding geographic patterns of genetic variation.

Journal Article↗

PubMed2006

Variation resources at UC Santa Cruz.

The variation resources within the University of California Santa Cruz Genome Browser include polymorphism data drawn from public collections and analyses of these data, along with their display in the context of other genomic annotations. Primary data from dbSNP is included for many organisms, with added information including genomic alleles and orthologous alleles for closely related organisms. Display filtering and coloring is available by variant type, functional class or other annotations. Annotation of potential errors is highlighted and a genomic alignment of the variant's flanking sequence is displayed. HapMap allele frequencies and linkage disequilibrium (LD) are available for each HapMap population, along with non-human primate alleles. The browsing and analysis tools, downloadable data files and links to documentation and other information can be found at http://genome.ucsc.edu/.

Alleles↗

PubMed2006

Forces shaping the fastest evolving regions in the human genome.

Comparative genomics allow us to search the human genome for segments that were extensively changed in the last approximately 5 million years since divergence from our common ancestor with chimpanzee, but are highly conserved in other species and thus are likely to be functional. We found 202 genomic elements that are highly conserved in vertebrates but show evidence of significantly accelerated substitution rates in human. These are mostly in non-coding DNA, often near genes associated with transcription and DNA binding. Resequencing confirmed that the five most accelerated elements are dramatically changed in human but not in other primates, with seven times more substitutions in human than in chimp. The accelerated elements, and in particular the top five, show a strong bias for adenine and thymine to guanine and cytosine nucleotide changes and are disproportionately located in high recombination and high guanine and cytosine content environments near telomeres, suggesting either biased gene conversion or isochore selection. In addition, there is some evidence of directional selection in the regions containing the two most accelerated regions. A combination of evolutionary forces has contributed to accelerated evolution of the fastest evolving elements in the human genome.

Animals↗

PubMed2006

An RNA gene expressed during cortical development evolved rapidly in humans.

The developmental and evolutionary mechanisms behind the emergence of human-specific brain features remain largely unknown. However, the recent ability to compare our genome to that of our closest relative, the chimpanzee, provides new avenues to link genetic and phenotypic changes in the evolution of the human brain. We devised a ranking of regions in the human genome that show significant evolutionary acceleration. Here we report that the most dramatic of these 'human accelerated regions', HAR1, is part of a novel RNA gene (HAR1F) that is expressed specifically in Cajal-Retzius neurons in the developing human neocortex from 7 to 19 gestational weeks, a crucial period for cortical neuron specification and migration. HAR1F is co-expressed with reelin, a product of Cajal-Retzius neurons that is of fundamental importance in specifying the six-layer structure of the human cortex. HAR1 and the other human accelerated regions provide new candidates in the search for uniquely human biology.

Aging↗

PubMed2006

Novel genes derived from noncoding DNA in Drosophila melanogaster are frequently X-linked and exhibit testis-biased expression.

Descriptions of recently evolved genes suggest several mechanisms of origin including exon shuffling, gene fission/fusion, retrotransposition, duplication-divergence, and lateral gene transfer, all of which involve recruitment of preexisting genes or genetic elements into new function. The importance of noncoding DNA in the origin of novel genes remains an open question. We used the well annotated genome of the genetic model system Drosophila melanogaster and genome sequences of related species to carry out a whole-genome search for new D. melanogaster genes that are derived from noncoding DNA. Here, we describe five such genes, four of which are X-linked. Our RT-PCR experiments show that all five putative novel genes are expressed predominantly in testes. These data support the idea that these novel genes are derived from ancestral noncoding sequence and that new, favored genes are likely to invade populations under selective pressures relating to male reproduction.

Animals↗

PubMed2005

Evolutionary genomics: codon bias and selection on single genomes.

The idea that natural selection on genes might be detected using only a single genome has been put forward by Plotkin and colleagues, who present a method that they claim can detect selection without the need for comparative data and which, if correct, would confer greater power of analysis with less information. Here we argue that their method depends on assumptions that confound their conclusions and that, even if these assumptions were valid, the authors' inferences about adaptive natural selection are unjustified.

Bias↗

PubMed2004

Comparative genomics of centrality and essentiality in three eukaryotic protein-interaction networks.

Most proteins do not evolve in isolation, but as components of complex genetic networks. Therefore, a protein's position in a network may indicate how central it is to cellular function and, hence, how constrained it is evolutionarily. To look for an effect of position on evolutionary rate, we examined the protein-protein interaction networks in three eukaryotes: yeast, worm, and fly. We find that the three networks have remarkably similar structure, such that the number of interactors per protein and the centrality of proteins in the networks have similar distributions. Proteins that have a more central position in all three networks, regardless of the number of direct interactors, evolve more slowly and are more likely to be essential for survival. Our results are thus consistent with a classic proposal of Fisher's that pleiotropy constrains evolution.

Biological Evolution↗

PubMed2004

Mechanisms and convergence of compensatory evolution in mammalian mitochondrial tRNAs.

The function of protein and RNA molecules depends on complex epistatic interactions between sites. Therefore, the deleterious effect of a mutation can be suppressed by a compensatory second-site substitution. In relating a list of 86 pathogenic mutations in human tRNAs encoded by mitochondrial genes to the sequences of their mammalian orthologs, we noted that 52 pathogenic mutations were present in normal tRNAs of one or several nonhuman mammals. We found at least five mechanisms of compensation for 32 pathogenic mutations that destroyed a Watson-Crick pair in one of the four tRNA stems: restoration of the affected Watson-Crick interaction (25 cases), strengthening of another pair (4 cases), creation of a new pair (8 cases), changes of multiple interactions in the affected stem (11 cases) and changes involving the interaction between the loop and stem structures (3 cases). A pathogenic mutation and its compensating substitution are fixed in a lineage in rapid succession, and often a compensatory interaction evolves convergently in different clades. At least 10%, and perhaps as many as 50%, of all nucleotide substitutions in evolving mammalian tRNAs participate in such interactions, indicating that the evolution of tRNAs proceeds along highly epistatic fitness ridges.

Animals↗

PubMed2004

Patterns of polymorphism and divergence from noncoding sequences of Drosophila melanogaster and D. simulans: evidence for nonequilibrium processes.

Despite the fact that D. melanogaster and D. simulans have been the central model system for molecular population genetics, few data are available for noncoding regions. Here, we present an analysis of population genetic data from intergenic regions and comparisons of these data to previously collected data from introns and exons. Polymorphisms and fixations were categorized as A/T to G/C or G/C to A/T changes and were polarized by inferring the ancestral state using both parsimony and maximum likelihood. Noncoding fixations in both D. melanogaster and D. simulans were consistent with equilibrium base-composition evolution. However, polarized noncoding polymorphisms, revealed a different pattern. Although A/T to G/C and G/C to A/T polymorphisms in D. simulans were consistent with equilibrium, we observed a highly significant dearth of A/T to G/C polymorphisms in D. melanogaster introns but not in intergenic sequences. Such data could be explained by recent evolution of mutational biases associated with transcription or by lineage-specific selection on base composition. These data reveal the complexity of evolutionary processes acting even on noncoding DNA in Drosophila.

Animals↗

PubMed2004

Molecular population genetics of male accessory gland proteins in the Drosophila simulans complex.

Accessory gland proteins are a major component of Drosophila seminal fluid. These proteins have a variety of functions and may be subject to sexual selection and/or antagonistic evolution between the sexes. Most population genetic data from these proteins are from D. melanogaster and D. simulans. Here, we extend the population genetic analysis of Acp genes to the other simulans complex species, D. mauritiana and D. sechellia. We sequenced population samples of seven Acp's from D. mauritiana, D. sechellia, and D. simulans. We investigated the population genetics of these genes on individual simulans complex lineages and compared Acp polymorphism and divergence to polymorphism and divergence from a set of non-Acp loci in the same species. Polymorphism and divergence data from the simulans complex revealed little evidence for adaptive protein evolution at individual loci. However, we observed a dramatically inflated index of dispersion for amino acid substitutions in the simulans complex at Acp genes, but not at non-Acp genes. This pattern of episodic bursts of protein evolution in Acp's provides the strongest evidence to date that the population genetic mechanisms driving Acp divergence are different from the mechanisms driving evolution at most Drosophila genes.

Animals↗

PubMed2002

The crystal structure of YdcE, a 4-oxalocrotonate tautomerase homologue from Escherichia coli, confirms the structural basis for oligomer diversity.

The tautomerase superfamily consists of three major families represented by 4-oxalocrotonate tautomerase (4-OT), 5-(carboxymethyl)-2-hydroxymuconate isomerase (CHMI), and macrophage migration inhibitory factor (MIF). The members of this superfamily are structurally homologous proteins constructed from a simple beta-alpha-beta fold that share a key mechanistic feature; they use an amino-terminal proline, which has an unusually low pK(a), as the general base in a keto-enol tautomerization. Several new members of the 4-OT family have now been identified using PSI-BLAST and categorized into five subfamilies on the basis of multiple-sequence alignments and the conservation of key catalytic and structural residues. The members of subfamily 5, which includes a hypothetical protein designated YdcE from Escherichia coli, are predicted not to form hexamers. The crystal structure of YdcE has been determined to 1.35 A resolution and confirms that it is a dimer. In addition, YdcE complexed with (E)-2-fluoro-p-hydroxycinnamate, identified as a potent competitive inhibitor of this enzyme, as well as N-(2-hydroxyethyl)piperazine-N'-2-ethanesulfonic acid (HEPES) and benzoate are also presented. These latter crystal structures reveal the location of the active site and suggest a mechanism for the observed YdcE-catalyzed tautomerization reaction. The dimeric arrangement of YdcE represents a new structure in the 4-OT family and demonstrates structural diversity within the 4-OT family not previously reported.

Amino Acid Sequence↗

PubMed2002

Genomic effects of nucleotide substitutions in Drosophila simulans.

Selective fixation of beneficial mutations reduces levels of linked, neutral variation. The magnitude of this "hitchhiking effect" is determined by the strength of selection and the recombination rate between selected and neutral sites. Thus, depending on the values of these parameters and the frequency with which directional selection occurs, the genomic scale over which directional selection reduces levels of linked variation may vary widely. Here we present a permutation-based analysis of nucleotide polymorphisms and fixations in Drosophila simulans. We show evidence of pervasive small-scale hitchhiking effects in this lineage. Furthermore, our results reveal that different types of fixations are associated with different levels of linked variation.

Animals↗