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Biomedical subjects

A S Kondrashov

Publications and source records attributed to A S Kondrashov.

At least 19 recordsLinked to original sources
PubMed2001

Multidimensional epistasis and the disadvantage of sex.

Sex is thought to facilitate accumulation of initially rare beneficial mutations by allowing simultaneous allele replacements at many loci. However, this advantage of sex depends on a restrictive assumption that the fitness of a genotype is determined by fitness potential, a single intermediate variable to which all loci contribute additively, so that new alleles can accumulate in any order. Individual-based simulations of sexual and asexual populations reveal that under generic selection, sex often retards adaptive evolution. When new alleles are beneficial only if they accumulate in a prescribed order, a sexual population may evolve two or more times slower than an asexual population because only asexual reproduction allows some overlap of successive allele replacements. Many other fitness surfaces lead to an even greater disadvantage of sex. Thus, either sex exists in spite of its impact on the rate of adaptive allele replacements, or natural fitness surfaces have rather specific properties, at least at the scale of intrapopulation genetic variability.

Adaptation, Physiological↗
PubMed2001

Prediction of deleterious human alleles.

Single nucleotide polymorphisms (SNPs) constitute the bulk of human genetic variation, occurring with an average density of approximately 1/1000 nucleotides of a genotype. SNPs are either neutral allelic variants or are under selection of various strengths, and the impact of SNPs on fitness remains unknown. Identification of SNPs affecting human phenotype, especially leading to risks of complex disorders, is one of the key problems of medical genetics. SNPs in protein-coding regions that cause amino acid variants (non-synonymous cSNPs) are most likely to affect phenotypes. We have developed a straightforward and reliable method based on physical and comparative considerations that estimates the impact of an amino acid replacement on the three-dimensional structure and function of the protein. We estimate that approximately 20% of common human non-synonymous SNPs damage the protein. The average minor allele frequency of such SNPs in our data set was two times lower than that of benign non-synonymous SNPs. The average human genotype carries approximately 10(3) damaging non-synonymous SNPs that together cause a substantial reduction in fitness.

Alleles↗
PubMed2001

Sex and U.

Resolution of several unsettled problems in genetics depends on the genomic rate of deleterious mutation, U. Selection against mutations can be a major factor in evolution only if U > or =1. Recently, significant progress has been made in measuring U in multicellular eukaryotes. An indirect estimate, based on a human-chimpanzee pseudogene comparison, produced U>3 for hominoids. By contrast, an estimate for Drosophila based on comparison of synonymous protein-coding sites produced U<0.1. However, the Drosophila figure might be underestimated because of selection at synonymous sites. Perhaps, the best way to measure U is to observe mutations shortly after they appear. So far, this direct approach has been applied only to humans and Caenorhabditis elegans, yielding high estimates of mutation rates.

Animals↗
PubMed2001

Selective constraint in intergenic regions of human and mouse genomes.

We aligned and analyzed 100 pairs of complete, orthologous intergenic regions from the human and mouse genomes (average length approximately 12 000 nucleotides). The alignments alternate between highly similar segments and dissimilar segments, indicating a wide variation of selective constraint. The average number of selectively constrained nucleotides within a mammalian intergenic region is at least 2000. This is threefold higher than within a nematode intergenic region and at least twofold higher than the number of selectively constrained nucleotides coding for an average protein. Because mammals possess only two- to threefold more proteins than Caenorhabditis elegans, the higher complexity of mammals might be primarily because of the functioning of intergenic DNA.

Animals↗
PubMed2001

Whole-genome effects of ethyl methanesulfonate-induced mutation on nine quantitative traits in outbred Drosophila melanogaster.

We induced mutations in Drosophila melanogaster males by treating them with 21.2 mm ethyl methanesulfonate (EMS). Nine quantitative traits (developmental time, viability, fecundity, longevity, metabolic rate, motility, body weight, and abdominal and sternopleural bristle numbers) were measured in outbred heterozygous F3 (viability) or F2 (all other traits) offspring from the treated males. The mean values of the first four traits, which are all directly related to the life history, were substantially affected by EMS mutagenesis: the developmental time increased while viability, fecundity, and longevity declined. In contrast, the mean values of the other five traits were not significantly affected. Rates of recessive X-linked lethals and of recessive mutations at several loci affecting eye color imply that our EMS treatment was equivalent to approximately 100 generations of spontaneous mutation. If so, our data imply that one generation of spontaneous mutation increases the developmental time by 0.09% at 20 degrees and by 0.04% at 25 degrees, and reduces viability under harsh conditions, fecundity, and longevity by 1.35, 0.21, and 0.08%, respectively. Comparison of flies with none, one, and two grandfathers (or greatgrandfathers, in the case of viability) treated with EMS did not reveal any significant epistasis among the induced mutations.

Alleles↗
PubMed2001

Molecular nature of 11 spontaneous de novo mutations in Drosophila melanogaster.

To investigate the molecular nature and rate of spontaneous mutation in Drosophila melanogaster, we screened 887,000 individuals for de novo recessive loss-of-function mutations at eight loci that affect eye color. In total, 28 mutants were found in 16 independent events (13 singletons and three clusters). The molecular nature of the 13 events was analyzed. Coding exons of the locus were affected by insertions or deletions >100 nucleotides long (6 events), short frameshift insertions or deletions (4 events), and replacement nucleotide substitutions (1 event). In the case of 2 mutant alleles, coding regions were not affected. Because approximately 70% of spontaneous de novo loss-of-function mutations in Homo sapiens are due to nucleotide substitutions within coding regions, insertions and deletions appear to play a much larger role in spontaneous mutation in D. melanogaster than in H. sapiens. If so, the per nucleotide mutation rate in D. melanogaster may be lower than in H. sapiens, even if their per locus mutation rates are similar.

Alleles↗
PubMed2001

Genome alignment, evolution of prokaryotic genome organization, and prediction of gene function using genomic context.

Gene order in prokaryotes is conserved to a much lesser extent than protein sequences. Only several operons, primarily those that code for physically interacting proteins, are conserved in all or most of the bacterial and archaeal genomes. Nevertheless, even the limited conservation of operon organization that is observed can provide valuable evolutionary and functional clues through multiple genome comparisons. A program for constructing gapped local alignments of conserved gene strings in two genomes was developed. The statistical significance of the local alignments was assessed using Monte Carlo simulations. Sets of local alignments were generated for all pairs of completely sequenced bacterial and archaeal genomes, and for each genome a template-anchored multiple alignment was constructed. In most pairwise genome comparisons, <10% of the genes in each genome belonged to conserved gene strings. When closely related pairs of species (i.e., two mycoplasmas) are excluded, the total coverage of genomes by conserved gene strings ranged from <5% for the cyanobacterium Synechocystis sp to 24% for the minimal genome of Mycoplasma genitalium, and 23% in Thermotoga maritima. The coverage of the archaeal genomes was only slightly lower than that of bacterial genomes. The majority of the conserved gene strings are known operons, with the ribosomal superoperon being the top-scoring string in most genome comparisons. However, in some of the bacterial-archaeal pairs, the superoperon is rearranged to the extent that other operons, primarily those subject to horizontal transfer, show the greatest level of conservation, such as the archaeal-type H+-ATPase operon or ABC-type transport cassettes. The level of gene order conservation among prokaryotic genomes was compared to the cooccurrence of genomes in clusters of orthologous genes (COGs) and to the conservation of protein sequences themselves. Only limited correlation was observed between these evolutionary variables. Gene order conservation shows a much lower variance than the cooccurrence of genomes in COGs, which indicates that intragenome homogenization via recombination occurs in evolution much faster than intergenome homogenization via horizontal gene transfer and lineage-specific gene loss. The potential of using template-anchored multiple-genome alignments for predicting functions of uncharacterized genes was quantitatively assessed. Functions were predicted or significantly clarified for approximately 90 COGs (approximately 4% of the total of 2414 analyzed COGs). The most significant predictions were obtained for the poorly characterized archaeal genomes; these include a previously uncharacterized restriction-modification system, a nuclease-helicase combination implicated in DNA repair, and the probable archaeal counterpart of the eukaryotic exosome. Multiple genome alignments are a resource for studies on operon rearrangement and disruption, which is central to our understanding of the evolution of prokaryotic genomes. Because of the rapid evolution of the gene order, the potential of genome alignment for prediction of gene functions is limited, but nevertheless, such predictions information significantly complements the results obtained through protein sequence and structure analysis.

Computational Biology↗
PubMed2000

Interkingdom gene fusions.

BACKGROUND: Genome comparisons have revealed major lateral gene transfer between the three primary kingdoms of life - Bacteria, Archaea, and Eukarya. Another important evolutionary phenomenon involves the evolutionary mobility of protein domains that form versatile multidomain architectures. We were interested in investigating the possibility of a combination of these phenomena, with an invading gene merging with a pre-existing gene in the recipient genome. RESULTS: Complete genomes of fifteen bacteria, four archaea and one eukaryote were searched for interkingdom gene fusions (IKFs); that is, genes coding for proteins that apparently consist of domains originating from different primary kingdoms. Phylogenetic analysis supported 37 cases of IKF, each of which includes a 'native' domain and a horizontally acquired 'alien' domain. IKFs could have evolved via lateral transfer of a gene coding for the alien domain (or a larger protein containing this domain) followed by recombination with a native gene. For several IKFs, this scenario is supported by the presence of a gene coding for a second, stand-alone version of the alien domain in the recipient genome. Among the genomes investigated, the greatest number of IKFs has been detected in Mycobacterium tuberculosis, where they are almost always accompanied by a stand-alone alien domain. For most of the IKF cases detected in other genomes, the stand-alone counterpart is missing. CONCLUSIONS: The results of comparative genome analysis show that IKF formation is a real, but relatively rare, evolutionary phenomenon. We hypothesize that IKFs are formed primarily via the proposed two-stage mechanism, but other than in the Actinomycetes, in which IKF generation seems to be an active, ongoing process, most of the stand-alone intermediates have been eliminated, perhaps because of functional redundancy.

Acetyltransferases↗
PubMed1999

Interactions among quantitative traits in the course of sympatric speciation.

Sympatric speciation, the origin of two or more species from a single local population, has almost certainly been involved in formation of several species flocks, and may be fairly common in nature. The most straightforward scenario for sympatric speciation requires disruptive selection favouring two substantially different phenotypes, and consists of the evolution of reproductive isolation between them followed by the elimination of all intermediate phenotypes. Here we use the hypergeometric phenotypic model to show that sympatric speciation is possible even when fitness and mate choice depend on different quantitative traits, so that speciation must involve formation of covariance between these traits. The increase in the number of variable loci affecting fitness facilitates sympatric speciation, whereas the increase in the number of variable loci affecting mate choice has the opposite effect. These predictions may enable more cases of sympatric speciation to be identified.

Animals↗
PubMed1999

Comparative genomics and evolutionary biology.

Data of large-scale DNA sequencing are relevant to some of the most fundamental issues in evolutionary biology: suboptimality, homology, hierarchy, ancestry, novelties, the role of natural selection, and the relative importance of directional versus stabilizing selection. Already, these data provided the best available evidence for some evolutionary phenomena, and in several cases led to refinement of old concepts. Still, the Darwinian evolutionary paradigm will successfully accommodate comparative genomics.

Animals↗
PubMed1999

Pattern of selective constraint in C. elegans and C. briggsae genomes.

Similarity between related genomes may carry information on selective constraint in each of them. We analysed patterns of similarity between several homologous regions of Caenorhabditis elegans and C. briggsae genomes. All homologous exons are quite similar. Alignments of introns and of intergenic sequences contain long gaps, segments where similarity is low and close to that between random sequences aligned using the same parameters, and segments of high similarity. Conservative estimates of the fractions of selectively constrained nucleotides are 72%, 17% and 18% for exons, introns and intergenic sequences, respectively. This implies that the total number of constrained nucleotides within non-coding sequences is comparable to that within coding sequences, so that at least one-third of nucleotides in C. elegans and C. briggsae genomes are under strong stabilizing selection.

Animals↗
PubMed1998

On the origin of species by means of assortative mating.

Assortative mating may split a population even in the absence of natural selection. Here, we study when this happens if mating depends on one or two quantitative traits. Not surprisingly, the modes of assortative mating that can cause sympatric speciation without selection are rather strict. However, some of them may occur in nature. Slow elimination of intermediate individuals caused by the gradual tightening of assortative mating, which evolves owing to relatively weak disruptive selection, provides the alternative scenario for sympatric speciation, in addition to fast elimination of intermediate individuals as a result of the direct action of strong disruptive selection under an invariant mode of assortative mating. Even when assortative mating alone cannot split an initially coherent population, it may be able to prevent the merging of species after their secondary contact.

Animals↗
PubMed1998

Measuring spontaneous deleterious mutation process.

Parameters of the deleterious mutation process can be estimated using the data on genotypes, phenotypes, or fitnesses. These data can be on long-term evolution, on short-term changes, or on the properties of equilibrium populations. The two most important parameters at the genomic level, the total deleterious mutation rate U and the mutational pressure on fitness P, remain poorly known. Reliable data on the rates of presumably neutral evolution, together with less certain estimates of the functionally important fraction of the genome, suggest that in mammals U > 1. The magnitudes of inbreeding depression in populations of selfers imply U approximately 1 in flowering plants. The straightforward way to estimate P is to assay the decline of fitness in populations with relaxed selection. The relevant data are contradictory, possibly because the results of the measurement of fitness depend strongly on the environmental conditions.

Animals↗
PubMed1997

Rapid decline of fitness in panmictic populations of Drosophila melanogaster maintained under relaxed natural selection.

The parameters of the spontaneous deleterious mutation process remain poorly known, despite their importance. Here, we report the results of a mutation accumulation experiment performed on panmictic populations of Drosophila melanogaster without any genetic manipulations. Two experimental populations were kept for 30 generations under relaxed natural selection. Each generation, 100 pairs were formed randomly, and every fecund pair contributed a son and a daughter to the next generation. Comparison with two controls, one cryopreserved and the other kept as the experimental populations but with long generation time, showed that the number of surviving offspring per female declined by 0.2% and 2.0% per generation under benign and harsh, competitive conditions, respectively. Thus, the mutational pressure on fitness may be strong and depends critically on the conditions under which fitness is assayed.

Animals↗
PubMed1997

The effect of cryopreservation on the lethal mutation rate in Drosophila melanogaster.

Although cryopreservation is routinely used for the storage of a range of biological organisms, few studies have been conducted to determine whether cryopreservation increases the frequency of mutation. A procedure for the cryopreservation of Drosophila melanogaster embryos has recently been developed. Cryopreservation of D. melanogaster is of special interest to geneticists and evolutionary biologists because it would make it possible to assay control and experimental populations simultaneously during long-term studies. Before cryopreserved embryos can be used for such studies, it is first necessary to show that cryopreservation is not mutagenic. We tested for mutagenic effects or cryopreservation in D. melanogaster embryos with an X-linked, recessive lethal assay. The mutation rates of cryopreserved and control flies were not significantly different. We can be 95% certain that cryopreservation does not increase mutation by a factor greater than 2.39. This is the first quantitative estimate of the mutagenic effect of cryopreservation on the germ line of a metazoan. The results are reassuring when considering the genetic impact of cryopreservation on mammalian gametes and embryos.

Animals↗
PubMed1995

Contamination of the genome by very slightly deleterious mutations: why have we not died 100 times over?

It is well known that when s, the selection coefficient against a deleterious mutation, is below approximately 1/4Ne, where Ne is the effective population size, the expected frequency of this mutation is approximately 0.5, if forward and backward mutation rates are similar. Thus, if the genome size, G, in nucleotides substantially exceeds the Ne of the whole species, there is a dangerous range of selection coefficients, 1/G < s < 1/4Ne. Mutations with s within this range are neutral enough to accumulate almost freely, but are still deleterious enough to make an impact at the level of the whole genome. In many vertebrates Ne approximately 10(4), while G approximately 10(9), so that the dangerous range includes more than four orders of magnitude. If substitutions at 10% of all nucleotide sites have selection coefficients within this range with the mean 10(-6), an average individual carries approximately 100 lethal equivalents. Some data suggest that a substantial fraction of nucleotides typical to a species may, indeed, be suboptimal. When selection acts on different mutations independently, this implies too high a mutation load. This paradox cannot be resolved by invoking beneficial mutations or environmental fluctuations. Several possible resolutions are considered, including soft selection and synergistic epistasis among very slightly deleterious mutations.

Animals↗