Search

Background: A substantial fraction of non-coding DNA sequences of multicellular eukaryotes is under selective constraint. In particular, ~;5 percent of the human genome consists of conserved non-coding sequences (CNSs). CNSs differ from other genomic sequences in their nucleotide composition and must play important functional roles, which mostly remain obscure.Results: We investigated relative abundances of short sequence motifs in all human CNSs present in the human/mouse whole-genome alignments vs. three background sets of sequences: (i) weakly conserved or unconserved non-coding sequences (non-CNSs); (ii) near-promoter sequences (located between nucleotides -500 and -1500, relative to a start of transcription); and (iii) random sequences with the same nucleotide composition as that of CNSs. When compared to non-CNSs and near-promoter sequences, CNSs possess an excess of AT-rich motifs, often containing runs of identical nucleotides. In contrast, when compared to random sequences, CNSs contain an excess of GC-rich motifs which, however, lack CpG dinucleotides. Thus, abundance of short sequence motifs in human CNSs, taken as a whole, is mostly determined by their overall compositional properties and not by overrepresentation of any specific short motifs. These properties are: (i) high AT-content of CNSs, (ii) a tendency, probably due to context-dependent mutation, of A's and T's to clump, (iii) presence of short GC-rich regions, and (iv) avoidance of CpG contexts, due to their hypermutability. Only a small number of short motifs, overrepresented in all human CNSs are similar to binding sites of transcription factors from the FOX family.Conclusion: Human CNSs as a whole appear to be too broad a class of sequences to possess strong footprints of any short sequence-specific functions. Such footprints should be studied at the level of functional subclasses of CNSs, such as those which flank genes with a particular pattern of expression. Overall properties of CNSs are affected by patterns in mutation, suggesting that selection which causes their conservation is not always very strong.

Fitness landscapes (1,2) depict how genotypes manifest at the phenotypic level and form the basis of our understanding of many areas of biology (2-7), yet their properties remain elusive. Previous [...]

The article describes the scheme for continual improvement of manufacturing quality spur gears in terms of error profiles of the side surfaces of gear teeth. The technique is universal and applicable to any operations of gear processing. The practical application of the technique is considered by the example of gear milling with a worm gear cutter. The errors of profile include metrological indicators of total error profile, the error direction and error of form profile. The scheme of analysis of the data consists of several steps – evaluation of indicators relative to the limit values, identification of the technological structure of the profile errors and expert analysis of the profile profilograms. The final expert analysis of profilograms allows to reveal the most probable operating negative technological factors leading to deviations of a profile from nominal position. The advantage of the quality improvement scheme is its high efficiency and effectiveness in comparison with traditional methods of statistical quality management, since it does not require the collection of significant amounts of statistical information.

A long-standing controversy in evolutionary biology is whether or not evolving lineages can cross valleys on the fitness landscape that correspond to low-fitness genotypes, which can eventually enable them to reach isolated fitness peaks (1-9). Here we study the fitness landscapes traversed by switches between different AU and GC Watson-Crick nucleotide pairs at complementary sites of mitochondrial transfer RNA stem regions in 83 mammalian species. We find that such Watson--Crick switches occur 30-40 times more slowly than pairs of neutral substitutions, and that alleles corresponding to GU and AC non-Watson--Crick intermediate states segregate within human populations at low frequencies, similar to those of non-synonymous alleles. Substitutions leading to a Watson--Crick switch are strongly correlated, especially in mitochondrial tRNAs encoded on the GT-nucleotide-rich strand of the mitochondrial genome. Using these data we estimate that a typical Watson--Crick switch involves crossing a fitness valley of a depth of about [10.sup.-3] or even about [10.sup.-2], with AC intermediates being slightly more deleterious than GU intermediates. This compensatory evolution must proceed through rare intermediate variants that never reach fixation (2). The ubiquitous nature of compensatory evolution in mammalian mitochondrial tRNAs and other molecules (10,11) implies that simultaneous fixation of two alleles that are individually deleterious may be a common phenomenon at the molecular level., When fitness is affected by complex interactions between alleles at different loci, an evolving lineage must navigate an epistatic fitness landscape (1,12,13). The most basic mode of epistasis is the [...]

The existing theory of sympatric speciation assumes that a local population splits into two species under one-dimensional disruptive selection, which favors both of the opposite extreme values of a quantitative trait. Here we model sympatric speciation under selection that favors high values of either of the two independently inherited traits, each required to efficiently consume one of the two available resources, but acts, because of a tradeoff, against those possessing high values of both traits. Such two-dimensional incompatibility selection is similar to that involved in allopatric speciation. Using a hypergeometric phenotypic model, we show that incompatibility selection readily leads to sympatric speciation. In contrast to disruptive selection, two distinct modes of sympatric speciation exist under incompatibility selection: under strong tradeoffs both of the new species are specialists, each consuming its own resource, but under moderate tradeoffs speciation may be asymmetric and involve the origin of a specialist and a generalist species. Also, incompatibility selection may lead to irreversible specialization: under strong tradeoffs, the population speciates if it consists mostly of unspecialized individuals, but remains undivided if most of the individuals are specialized to consume one of the resources. Incompatibility selection appears to be more realistic than disruptive selection, implying that incompatibility between individually adaptive alleles or trait states drives both allopatric and sympatric speciation. evolution | tradeoff | resource | hypergeometric model

Persistence time of a mutant allele, the expected number of generations before its elimination from the population, can be estimated as the ratio of the number of segregating mutations per individual over the mutation rate per generation. We screened two natural populations of Drosophila melanogaster for mutations causing clear-cut eye phenotypes and detected 25 mutant alleles, falling into 19 complementation groups, in 1164 haploid genomes, which implies 0.021 eye mutations/genome. The de novo haploid mutation rate for the same set of loci was estimated as 2 X [10.sup.-4] in a 10-generation mutation-accumulation experiment. Thus, the average persistence time of all mutations causing clear-cut eye phenotypes is ~100 generations (95% confidence interval: 61-219). This estimate shows that the strength of selection against phenotypically drastic alleles of nonessential loci is close to that against recessive lethals. In both cases, deleterious alleles are apparently eliminated by selection against heterozygous individuals, which show no visible phenotypic differences from wild type.

Author(s): I. King Jordan [1]; Fyodor A. Kondrashov [2]; Ivan A. Adzhubei [3]; Yuri I. Wolf [1]; Eugene V. Koonin [1]; Alexey S. Kondrashov (corresponding author) [1]; Shamil Sunyaev (corresponding [...]

Author(s): Georgii A. Bazykin (corresponding author) [1]; Fyodor A. Kondrashov [2]; Aleksey Y. Ogurtsov [3]; Shamil Sunyaev [4]; Alexey S. Kondrashov [3] New alleles become fixed owing to random drift [...]