Elucidating how natural selection promotes local adaptation in interaction with migration, genetic drift and mutation is a central aim of evolutionary biology. While several conceptual and practical limitations are still restraining our ability to study these processes at the DNA level, genes of the major histocompatibility complex (MHC) offer several assets that make them unique candidates for this purpose. Yet, it is unclear what general conclusions can be drawn after 15 years of empirical research that documented MHC diversity in the wild. The general objective of this review is to complement earlier literature syntheses on this topic by focusing on MHC studies other than humans and mice. This review first revealed a strong taxonomic bias, whereby many more studies of MHC diversity in natural populations have dealt with mammals than all other vertebrate classes combined. Secondly, it confirmed that positive selection has a determinant role in shaping patterns of nucleotide diversity in MHC genes in all vertebrates studied. Yet, future tests of positive selection would greatly benefit from making better use of the increasing number of models potentially offering more statistical rigour and higher resolution in detecting the effect and form of selection. Thirdly, studies that compared patterns of MHC diversity within and among natural populations with neutral expectations have reported higher population differentiation at MHC than expected either under neutrality or simple models of balancing selection. Fourthly, several studies showed that MHC-dependent mate preference and kin recognition may provide selective factors maintaining polymorphism in wild outbred populations. However, they also showed that such reproductive mechanisms are complex and context-based. Fifthly, several studies provided evidence that MHC may significantly influence fitness, either by affecting reproductive success or progeny survival to pathogens infections. Overall, the evidence is compelling that the MHC currently represents the best system available in vertebrates to investigate how natural selection can promote local adaptation at the gene level despite the counteracting actions of migration and genetic drift. We conclude this review by proposing several directions where future research is needed.

Protein interactions regulate the systems-level behavior of cells; thus, deciphering the structure and dynamics of protein interaction networks in their cellular context is a central goal in biology. We have performed a genome-wide in vivo screen for protein-protein interactions in Saccharomyces cerevisiae by means of a protein-fragment complementation assay (PCA). We identified 2770 interactions among 1124 endogenously expressed proteins. Comparison with previous studies confirmed known interactions, but most were not known, revealing a previously unexplored subspace of the yeast protein interactome. The PCA detected structural and topological relationships between proteins, providing an 8-nanometer-resolution map of dynamically interacting complexes in vivo and extended networks that provide insights into fundamental cellular processes, including cell polarization and autophagy, pathways that are evolutionarily conserved and central to both development and human health.T he elucidation of protein-protein interaction networks (PINs, or interactomes) holds the promise of answering fundamental questions about how the biochemical machinery of cells organizes matter, information, and energy transformations to perform specific functions (1). An essential and rarely addressed question is whether protein complexes and PINs that are reconstructed or reconstituted in vitro or removed from the normal context in which they are expressed reflect their organization in living cells. For eukaryotes, the test bed for large-scale analysis of PINs is the yeast Saccharomyces cerevisiae, where several PIN analyses have been performed using yeast two-hybrid screens (Y2H) (2-4) or tandem affinity purification followed by massspectrometric analyses (TAP-MSs) (5-8). Each approach captures specific features of protein interactions; two-hybrid methods are best at measuring direct binary interactions between pairs of proteins, whereas affinity purification techniques best capture stable protein complexes. However, neither approach measures interactions between proteins in their natural cellular context, and are not easily amenable to studying protein complexes that are transiently associated or dynamic under different conditions, that do not survive in vitro purification, or that cannot be transported to the nucleus and form interactions in the absence of other

The mutation process ultimately defines the genetic features of all populations and, hence, has a bearing on a wide range of issues involving evolutionary genetics, inheritance, and genetic disorders, including the predisposition to cancer. Nevertheless, formidable technical barriers have constrained our understanding of the rate at which mutations arise and the molecular spectrum of their effects. Here, we report on the use of complete-genome sequencing in the characterization of spontaneously arising mutations in the yeast Saccharomyces cerevisiae. Our results confirm some findings previously obtained by indirect methods but also yield numerous unexpected findings, in particular a very high rate of point mutation and skewed distribution of base-substitution types in the mitochondrion, a very high rate of segmental duplication and deletion in the nuclear genome, and substantial deviations in the mutational profile among various model organisms.chromosomal instability ͉ mitochondrion ͉ mutation rate ͉ mutational spectrum ͉ Saccharomyces cerevisiae D espite its relevance to every aspect of genetics and evolution, our understanding of the mutation process and its bearing on organismal fitness remains quite limited (1-4). Owing to the technical difficulties in directly observing very low-frequency events, most estimates of the per-nucleotide mutation rate are derived either from surveys of visible mutations at reporter loci (to enhance the detectability of mutations) or from nucleotide-sequence comparisons of silent sites in distantly related species (to magnify the accumulation of mutations). Neither approach is without problems, the first requiring assumptions about the fraction of mutations with observable phenotypic effects and the second relying on assumptions about interspecific divergence times, generation lengths, and neutrality of the monitored nucleotide sites.Long-term mutation-accumulation (MA) experiments, whereby replicate lines are taken through regular bottlenecks to minimize the efficiency of selection, have proven to be highly valuable resources for procuring spontaneous mutations in an essentially unbiased fashion (5-8). However, brute-force sequencing of PCR-amplified products constrains the number of mutations that can be detected in a reasonable amount of time. Here, we demonstrate the feasibility of whole-genome sequencing as a means to assay the complete spectrum of mutational effects in a moderately sized eukaryotic genome.Our analyses are based on an examination of parallel MA lines of a key model system, the yeast Saccharomyces cerevisiae. The initially isogenic lines were passed through 200 single-cell bottlenecks on a 3-to 4-day cycle of clonal growth for a total of Ϸ4,800 cell divisions per line [see supporting information (SI) Text]. Although there is some opportunity for the selective elimination of deleterious mutations during daily clonal amplification, this effect is quite small under the imposed bottlenecking procedure. For mutations with a relative selective disadvantage of s ϭ ...

Previous studies in Saccharomyces cerevisiae have demonstrated that cryptic promoters within coding regions activate transcription in particular mutants. We have performed a comprehensive analysis of cryptic transcription in order to identify factors that normally repress cryptic promoters, to determine the amount of cryptic transcription genome-wide, and to study the potential for expression of genetic information by cryptic transcription. Our results show that a large number of factors that control chromatin structure and transcription are required to repress cryptic transcription from at least 1,000 locations across the S. cerevisiae genome. Two results suggest that some cryptic transcripts are translated. First, as expected, many cryptic transcripts contain an ATG and an open reading frame of at least 100 codons. Second, several cryptic transcripts are translated into proteins. Furthermore, a subset of cryptic transcripts tested is transiently induced in wild-type cells following a nutritional shift, suggesting a possible physiological role in response to a change in growth conditions. Taken together, our results demonstrate that, during normal growth, the global integrity of gene expression is maintained by a wide range of factors and suggest that, under altered genetic or physiological conditions, the expression of alternative genetic information may occur.