Imprinted chromosomal regions of the human genome have unusually high recombination rates.
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Chromosomes, Human↗
Biomedical subjects
Martin J Lercher
Publications and source records attributed to Martin J Lercher.
Coexpression of neighboring genes in Caenorhabditis elegans is mostly due to operons and duplicate genes.
In many eukaryotic species, gene order is not random. In humans, flies, and yeast, there is clustering of coexpressed genes that cannot be explained as a trivial consequence of tandem duplication. In the worm genome this is taken a step further with many genes being organized into operons. Here we analyze the relationship between gene location and expression in Caenorhabditis elegans and find evidence for at least three different processes resulting in local expression similarity. Not surprisingly, the strongest effect comes from genes organized in operons. However, coexpression within operons is not perfect, and is influenced by some distance-dependent regulation. Beyond operons, there is a relationship between physical distance, expression similarity, and sequence similarity, acting over several megabases. This is consistent with a model of tandem duplicate genes diverging over time in sequence and expression pattern, while moving apart owing to chromosomal rearrangements. However, at a very local level, nonduplicate genes on opposite strands (hence not in operons) show similar expression patterns. This suggests that such genes may share regulatory elements or be regulated at the level of chromatin structure. The central importance of tandem duplicate genes in these patterns renders the worm genome different from both yeast and human.
Animals↗
Can mutation or fixation biases explain the allele frequency distribution of human single nucleotide polymorphisms (SNPs)?
One of the most abiding controversies in evolutionary biology concerns the role of neutral processes in molecular evolution. A main focus of the debate has been the evolution of isochores, the strong and systematic variation of base composition in mammalian genomes. One set of hypotheses argue that regions of similar GC are owing to localised mutational biases coupled with neutral evolution. The alternatives point to either selection or biased gene conversion as mechanisms to preferentially remove A or T bases, favouring G and C instead. Using a novel method, we compare models including such fixation biases to models based on mutation bias alone, under the assumption that non-coding, non-repetitive human DNA is at compositional equilibrium. While failing to fully explain the allele frequency distributions of recent single nucleotide polymorphism data, we show that the data are best fitted if the mutation bias is assumed to be constant across the genome, while fixation bias varies with GC content. We also attempt to estimate the strength of fixation bias, which increases linearly with increasing GC. Our approximation suggests that this force exists within the necessary parameter range: it is not so weak as to be drowned by random drift, but not so strong as to lead to exclusive use of G and C alone. Together these results demonstrate that mutation bias fails to explain the evolution of isochores, and suggest that either selection or biased gene conversion are involved.
Alleles↗
Clustering of housekeeping genes provides a unified model of gene order in the human genome.
It is often supposed that, except for tandem duplicates, genes are randomly distributed throughout the human genome. However, recent analyses suggest that when all the genes expressed in a given tissue (notably placenta and skeletal muscle) are examined, these genes do not map to random locations but instead resolve to clusters. We have asked three questions: (i) is this clustering true for most tissues, or are these the exceptions; (ii) is any clustering simply the result of the expression of tandem duplicates and (iii) how, if at all, does this relate to the observed clustering of genes with high expression rates? We provide a unified model of gene clustering that explains the previous observations. We examined Serial Analysis of Gene Expression (SAGE) data for 14 tissues and found significant clustering, in each tissue, that persists even after the removal of tandem duplicates. We confirmed clustering by analysis of independent expressed-sequence tag (EST) data. We then tested the possibility that the human genome is organized into subregions, each specializing in genes needed in a given tissue. By comparing genes expressed in different tissues, we show that this is not the case: those genes that seem to be tissue-specific in their expression do not, as a rule, cluster. We report that genes that are expressed in most tissues (housekeeping genes) show strong clustering. In addition, we show that the apparent clustering of genes with high expression rates is a consequence of the clustering of housekeeping genes.
Gene Order↗
Regional similarities in polymorphism in the human genome extend over many megabases.
The human genome exhibits extensive regional variation both in base composition and in the synonymous and nonsynonymous substitution rates of protein-coding genes. If such regional variation is due to variation in mutation rates, then levels of polymorphism should also vary across the human genome. Building on recent advances in mapping the human genome, we demonstrate regional variation in single nucleotide polymorphism density extending over many megabases. The range of local similarity in polymorphism shown by our genome-wide study is similar to the range of local similarity in base composition, and occurs over much longer distances than the variation in polymorphism revealed by studies of linkage disequilibrium.
GC Rich Sequence↗
Human SNP variability and mutation rate are higher in regions of high recombination.
Understanding the co-variation of nucleotide diversity and local recombination rates is important both for the mapping of disease-associated loci and in understanding the causes of sequence evolution. It is known that single nucleotide polymorphisms (SNPs) around protein coding genes show higher diversity in regions of high recombination. Here, we find that this correlation holds for SNPs across the entire human genome, the great majority of which are not near exons or control elements. Contrasting with results from coding regions, we provide evidence that the higher nucleotide diversity in regions of high recombination is most likely due, at least in part, to a higher mutation rate. One possible explanation for this is that recombination is mutagenic.
Animals↗
The evolution of isochores: evidence from SNP frequency distributions.
The large-scale systematic variation in nucleotide composition along mammalian and avian genomes has been a focus of the debate between neutralist and selectionist views of molecular evolution. Here we test whether the compositional variation is due to mutation bias using two new tests, which do not assume compositional equilibrium. In the first test we assume a standard population genetics model, but in the second we make no assumptions about the underlying population genetics. We apply the tests to single-nucleotide polymorphism data from noncoding regions of the human genome. Both models of neutral mutation bias fit the frequency distributions of SNPs segregating in low- and medium-GC-content regions of the genome adequately, although both suggest compositional nonequilibrium. However, neither model fits the frequency distribution of SNPs from the high-GC-content regions. In contrast, a simple population genetics model that incorporates selection or biased gene conversion cannot be rejected. The results suggest that mutation biases are not solely responsible for the compositional biases found in noncoding regions.
Alleles↗