Biomedical subjects

Kateryna D Makova

Publications and source records attributed to Kateryna D Makova.

13 recordsLinked to original sources

PubMed2026

Nuclear mitochondrial sequences in great ape telomere-to-telomere genomes.

Mitochondrial sequences have integrated into the nuclear genome since the origin of eukaryotes. Recent insertions that retain homology with extant mitochondrial DNA (mtDNA), termed NUMTs, confound mtDNA sequence analysis. Here, we use great ape telomere-to-telomere (T2T) genomes to study NUMTs in bonobo, chimpanzee, human, gorilla, and Bornean and Sumatran orangutans. A phylogeny based on shared and lineage-specific NUMTs accurately recapitulates the great ape species tree topology. NUMTs are enriched at nonfunctional nonrepetitive regions of the nuclear genome and depleted within enhancers and coding sequences, suggesting negative selection. We validate the presence of a 76-kb-long heterozygous NUMT in chimpanzee, which is larger than any other NUMT observed in great apes, and find that dozens of NUMTs on the Pan Y Chromosome expanded together with palindromes. Finally, by analyzing intra-specific variation, we confirm that the vast majority of species-specific NUMTs identified in T2T assemblies are fixed or present at high frequencies in each species. Our study highlights NUMTs as a dynamic evolutionary force contributing to shaping ape genomes and is valuable for characterizing mtDNA in great apes.

Journal Article↗

PubMed2026

A complete genome for the common marmoset.

The common marmoset is a New World monkey widely used to study primate evolution and human disease. We present a telomere-to-telomere (T2T) reference assembly for the species, plus three near-T2T haplotypes. These resolve previously inaccessible regions, including the centromeres, sex chromosomes, subterminal satellites, acrocentric chromosomes, and the major histocompatibility complex (MHC). We find marmoset centromeres carry dimeric alpha satellites with chromosomal specificity, flanked by inactive layers interpreted as ancestral centromere remnants. We assemble gene-poor, satellite-rich short arms of the acrocentrics and find that most can harbor rDNA and all share pseudo-homolog regions (PHRs). PHR-sharing chromosomes also share closely related centromeric satellites, consistent with a model of ongoing rDNA-facilitated recombinational exchange between heterologous chromosomes. We further identify over 500 marmoset-lineage-specific transcribed genes with previously unknown transcript models or expansions. These resources, along with a preliminary pangenome, improve the utility of the marmoset as a model organism and address gaps in primate genome evolution.

Animals↗

PubMed2006

Mammalian male mutation bias: impacts of generation time and regional variation in substitution rates.

In mammals, males undergo a greater number of germline cell divisions compared with females. Thus, the male germline accumulates more DNA replication errors, which result in male mutation bias-a higher mutation rate for males than for females. The phenomenon of male mutation bias has been investigated mostly for rodents and primates, however, it has not been studied in detail for other mammalian orders. Here we sequenced and analyzed five introns of three genes (DBX/DBY, UTX/UTY, and ZFX/ZFY) homologous between X and Y chromosomes in several species of perissodactyls (horses and rhinos) and of primates. Male mutation bias was evident: substitution rate was higher for a Y chromosome intron than for its X chromosome homologue for all five intron pairs studied. Substitution rates varied regionally among introns sequenced on the same chromosome and this variation influenced male mutation bias inferred from each intron pair. Interestingly, we observed a positive correlation in substitution rates between homologous X and homologous Y introns as well as between orthologous primate and perissodactyl introns. The male-to-female mutation rate ratio estimated from concatenated sequences of five perissodactyl introns was 3.88 (95% CI = 2.90-6.07). Using the data generated here and estimates available in the literature, we compared male mutation bias among several mammalian orders. We conclude that male mutation bias is significantly higher for organisms with long generation times (primates, perissodactyls, and felids) than for organisms with short generation times (e.g., rodents) since the former undergo a greater number of male germline cell divisions.

Aging↗

PubMed2006

Genomic environment predicts expression patterns on the human inactive X chromosome.

What genomic landmarks render most genes silent while leaving others expressed on the inactive X chromosome in mammalian females? To date, signals determining expression status of genes on the inactive X remain enigmatic despite the availability of complete genomic sequences. Long interspersed repeats (L1s), particularly abundant on the X, are hypothesized to spread the inactivation signal and are enriched in the vicinity of inactive genes. However, both L1s and inactive genes are also more prevalent in ancient evolutionary strata. Did L1s accumulate there because of their role in inactivation or simply because they spent more time on the rarely recombining X? Here we utilize an experimentally derived inactivation profile of the entire human X chromosome to uncover sequences important for its inactivation, and to predict expression status of individual genes. Focusing on Xp22, where both inactive and active genes reside within evolutionarily young strata, we compare neighborhoods of genes with different inactivation states to identify enriched oligomers. Occurrences of such oligomers are then used as features to train a linear discriminant analysis classifier. Remarkably, expression status is correctly predicted for 84% and 91% of active and inactive genes, respectively, on the entire X, suggesting that oligomers enriched in Xp22 capture most of the genomic signal determining inactivation. To our surprise, the majority of oligomers associated with inactivated genes fall within L1 elements, even though L1 frequency in Xp22 is low. Moreover, these oligomers are enriched in parts of L1 sequences that are usually underrepresented in the genome. Thus, our results strongly support the role of L1s in X inactivation, yet indicate that a chromatin microenvironment composed of multiple genomic sequence elements determines expression status of X chromosome genes.

Algorithms↗

PubMed2006

Rapid and asymmetric divergence of duplicate genes in the human gene coexpression network.

BACKGROUND: While gene duplication is known to be one of the most common mechanisms of genome evolution, the fates of genes after duplication are still being debated. In particular, it is presently unknown whether most duplicate genes preserve (or subdivide) the functions of the parental gene or acquire new functions. One aspect of gene function, that is the expression profile in gene coexpression network, has been largely unexplored for duplicate genes. RESULTS: Here we build a human gene coexpression network using human tissue-specific microarray data and investigate the divergence of duplicate genes in it. The topology of this network is scale-free. Interestingly, our analysis indicates that duplicate genes rapidly lose shared coexpressed partners: after approximately 50 million years since duplication, the two duplicate genes in a pair have only slightly higher number of shared partners as compared with two random singletons. We also show that duplicate gene pairs quickly acquire new coexpressed partners: the average number of partners for a duplicate gene pair is significantly greater than that for a singleton (the latter number can be used as a proxy of the number of partners for a parental singleton gene before duplication). The divergence in gene expression between two duplicates in a pair occurs asymmetrically: one gene usually has more partners than the other one. The network is resilient to both random and degree-based in silico removal of either singletons or duplicate genes. In contrast, the network is especially vulnerable to the removal of highly connected genes when duplicate genes and singletons are considered together. CONCLUSION: Duplicate genes rapidly diverge in their expression profiles in the network and play similar role in maintaining the network robustness as compared with singletons.

Chromosome Mapping↗

PubMed2005

Strong and weak male mutation bias at different sites in the primate genomes: insights from the human-chimpanzee comparison.

Male mutation bias is a higher mutation rate in males than in females thought to result from the greater number of germ line cell divisions in males. If errors in DNA replication cause most mutations, then the magnitude of male mutation bias, measured as the male-to-female mutation rate ratio (alpha), should reflect the relative excess of male versus female germ line cell divisions. Evolutionary rates averaged among all sites in a sequence and compared between mammalian sex chromosomes were shown to be indeed higher in males than in females. However, it is presently unknown whether individual classes of substitutions exhibit such bias. To address this issue, we investigated male mutation bias separately at non-CpG and CpG sites using human-chimpanzee whole-genome alignments. We observed strong male mutation bias at non-CpG sites: alpha in the X-autosome comparison was approximately 6-7, which was similar to the male-to-female ratio in the number of germ line cell divisions. In contrast, mutations at CpG sites exhibited weak male mutation bias: alpha in the X-autosome comparison was only approximately 2-3. This is consistent with the methylation-induced and replication-independent mechanism of CpG transitions, which constitute the majority of mutations at CpG sites. Interestingly, our study also indicated weak male mutation bias for transversions at CpG sites, implying a spontaneous mechanism largely not associated with replication. Male mutation bias was equally strong at CpG and non-CpG sites located within unmethylated "CpG islands," suggesting the replication-dependent origin of these mutations. Thus, we found that the strength of male mutation bias is nonuniform in the primate genomes. Importantly, we discovered that male mutation bias depends on the proportion of CpG sites in the loci compared. This might explain the differences in the magnitude of primate male mutation bias observed among studies.

Animals↗

PubMed2005

Oscillating evolution of a mammalian locus with overlapping reading frames: an XLalphas/ALEX relay.

XLalphas and ALEX are structurally unrelated mammalian proteins translated from alternative overlapping reading frames of a single transcript. Not only are they encoded by the same locus, but a specific XLalphas/ALEX interaction is essential for G-protein signaling in neuroendocrine cells. A disruption of this interaction leads to abnormal human phenotypes, including mental retardation and growth deficiency. The region of overlap between the two reading frames evolves at a remarkable speed: the divergence between human and mouse ALEX polypeptides makes them virtually unalignable. To trace the evolution of this puzzling locus, we sequenced it in apes, Old World monkeys, and a New World monkey. We show that the overlap between the two reading frames and the physical interaction between the two proteins force the locus to evolve in an unprecedented way. Namely, to maintain two overlapping protein-coding regions the locus is forced to have high GC content, which significantly elevates its intrinsic evolutionary rate. However, the two encoded proteins cannot afford to change too quickly relative to each other as this may impair their interaction and lead to severe physiological consequences. As a result XLalphas and ALEX evolve in an oscillating fashion constantly balancing the rates of amino acid replacements. This is the first example of a rapidly evolving locus encoding interacting proteins via overlapping reading frames, with a possible link to the origin of species-specific neurological differences.

Amino Acid Sequence↗

PubMed2004

Insertions and deletions are male biased too: a whole-genome analysis in rodents.

It is presently accepted that, in mammals, due to the greater number of cell divisions in the male germline than in the female germline, nucleotide substitutions occur more frequently in males. The data on mutation bias in insertions and deletions (indels) are contradictory, with some studies indicating no sex bias and others indicating either female or male bias. The sequenced rat and mouse genomes provide a unique opportunity to investigate a potential sex bias for different types of mutations. Indeed, mutation rates can be accurately estimated from a large number of orthologous loci in organisms similar in generation time and in the number of germline cell divisions. Here we compare the mutation rates between chromosome X and autosomes for likely neutral sites in eutherian ancestral interspersed repetitive elements present at orthologous locations in the rat and mouse genomes. We find that small indels are male biased: The male-to-female mutation rate ratio (alpha) for indels in rodents is approximately 2. Similarly, our whole-genome analysis in rodents indicates an approximately twofold excess of nucleotide substitutions originating in males over that in females. This is the same as the male-to-female ratio of the number of germline cell divisions in rat and mouse. Thus, this is consistent with nucleotide substitutions and small indels occurring primarily during DNA replication.

Animals↗

PubMed2004

Comparative genomics.

The genomes from three mammals (human, mouse, and rat), two worms, and several yeasts have been sequenced, and more genomes will be completed in the near future for comparison with those of the major model organisms. Scientists have used various methods to align and compare the sequenced genomes to address critical issues in genome function and evolution. This review covers some of the major new insights about gene content, gene regulation, and the fraction of mammalian genomes that are under purifying selection and presumed functional. We review the evolutionary processes that shape genomes, with particular attention to variation in rates within genomes and along different lineages. Internet resources for accessing and analyzing the treasure trove of sequence alignments and annotations are reviewed, and we discuss critical problems to address in new bioinformatic developments in comparative genomics.

Animals↗

PubMed2003

Divergence in the spatial pattern of gene expression between human duplicate genes.

Microarray gene expression data provide a wealth of information for elucidating the mode and tempo of molecular evolution. In the present study,we analyze the spatial expression pattern of human duplicate gene pairs by using oligonucleotide microarray data,and study the relationship between coding sequence divergence and expression divergence. First,we find a strong positive correlation between the proportion of duplicate gene pairs with divergent expression (as presence or absence of expression in a tissue) and both synonymous (K(S)) and nonsynonymous divergence (K(A)). The divergence of gene expression between human duplicate genes is rapid, probably faster than that between yeast duplicates in terms of generations. Second,we compute the correlation coefficient (R) between the expression levels of duplicate genes in different tissues and find a significant negative correlation between R and K(S). There is also a negative correlation between R and K(A), when K(A) <or= 0.2. These results indicate that protein sequence divergence and divergence of spatial expression pattern are initially coupled. Finally,we compare the functions of those duplicate genes that show rapid divergence in spatial expression pattern with the functions of those duplicate genes that show no or little divergence in spatial expression.

Computational Biology↗

PubMed2002

Chromosome-wide SNPs reveal an ancient origin for Plasmodium falciparum.

The Malaria's Eve hypothesis, proposing a severe recent population bottleneck (about 3,000-5,000 years ago) of the human malaria parasite Plasmodium falciparum, has prompted a debate about the origin and evolution of the parasite. The hypothesis implies that the parasite population is relatively homogeneous, favouring malaria control measures. Other studies, however, suggested an ancient origin and large effective population size. To test the hypothesis, we analysed single nucleotide polymorphisms (SNPs) from 204 genes on chromosome 3 of P. falciparum. We have identified 403 polymorphic sites, including 238 SNPs and 165 microsatellites, from five parasite clones, establishing chromosome-wide haplotypes and a dense map with one polymorphic marker per approximately 2.3 kilobases. On the basis of synonymous SNPs and non-coding SNPs, we estimate the time to the most recent common ancestor to be approximately 100,000-180,000 years, significantly older than the proposed bottleneck. Our estimated divergence time coincides approximately with the start of human population expansion, and is consistent with a genetically complex organism able to evade host immunity and other antimalarial efforts.

Animals↗

PubMed2002

Strong male-driven evolution of DNA sequences in humans and apes.

Studies of human genetic diseases have suggested a higher mutation rate in males than in females and the male-to-female ratio (alpha) of mutation rate has been estimated from DNA sequence and microsatellite data to be about 4-6 in higher primates. Two recent studies, however, claim that alpha is only about 2 in humans. This is even smaller than the estimates (alpha > 4) for carnivores and birds; humans should have a higher alpha than carnivores and birds because of a longer generation time and a larger sex difference in the number of germ cell cycles. To resolve this issue, we sequenced a noncoding fragment on Y of about 10.4 kilobases (kb) and a homologous region on chromosome 3 in humans, greater apes, and lesser apes. Here we show that our estimate of alpha from the internal branches of the phylogeny is 5.25 (95% confidence interval (CI) 2.44 to infinity), similar to the previous estimates, but significantly higher than the two recent ones. In contrast, for the external (short, species-specific) branches, alpha is only 2.23 (95% CI: 1.47-3.84). We suggest that closely related species are not suitable for estimating alpha, because of ancient polymorphism and other factors. Moreover, we provide an explanation for the small estimate of alpha in a previous study. Our study reinstates a high alpha in hominoids and supports the view that DNA replication errors are the primary source of germline mutation.

Animals↗

PubMed2002

The K(A)/K(S) ratio test for assessing the protein-coding potential of genomic regions: an empirical and simulation study.

Comparative genomics is a simple, powerful way to increase the accuracy of gene prediction. In this study, we show the utility of a simple test for the identification of protein-coding exons using human/mouse sequence comparisons. The test takes advantage of the fact that in the vast majority of coding regions, synonymous substitutions (K(S)) occur much more frequently than nonsynonymous ones (K(A)) and uses the K(A)/K(S) ratio as the criterion. We show the following: (1) most of the human and mouse exons are sufficiently long and have a suitable degree of sequence divergence for the test to perform reliably; (2) the test is suited for the identification of long exons and single exon genes, which are difficult to predict by current methods; (3) the test has a false-negative rate, lower than most of current gene prediction methods and a false-positive rate lower than all current methods; (4) the test has been automated and can be used in combination with other existing gene-prediction methods.

Animals↗