Selective sweep at a quantitative trait locus in the presence of background genetic variation

We model selection at a locus affecting a quantitative trait (QTL) in the presence of genetic variance due to other loci. The dynamics at the QTL are related to the initial genotypic value and to the background genetic variance of the trait, assuming that background genetic values are normally distributed, under three different forms of selection on the trait. Approximate dynamics are derived under the assumption of small mutation effect. For similar strengths of selection on the trait (i.e, gradient of directional selection beta) the way background variation affects the dynamics at the QTL critically depends on the shape of the fitness function. It generally causes the strength of selection on the QTL to decrease with time. The resulting neutral heterozygosity pattern resembles that of a selective sweep with a constant selection coefficient corresponding to the early conditions. The signature of selection may also be blurred by mutation and recombination in the later part of the sweep. We also study the race between the QTL and its genetic background toward a new optimum and find the conditions for a complete sweep. Overall, our results suggest that phenotypic traits exhibiting clear-cut molecular signatures of selection may represent a biased subset of all adaptive traits.     

Joint effects of genetic hitchhiking and background selection on neutral variation

Due to relatively high rates of strongly selected deleterious mutations, directional selection on favorable alleles (causing hitchhiking effects on linked neutral polymorphisms) is expected to occur while a deleterious mutation-selection balance is present in a population. We analyze this interaction of directional selection and background selection and study their combined effects on neutral variation, using a three-locus model in which each locus is subjected to either deleterious, favorable, or neutral mutations. Average heterozygosity is measured by simulations (1) at the stationary state under the assumption of recurrent hitchhiking events and (2) as a transient level after a single hitchhiking event. The simulation results are compared to theoretical predictions. It is shown that known analytical solutions describing the hitchhiking effect without background selection can be modified such that they accurately predict the joint effects of hitchhiking and background on linked, neutral variation. Generalization of these results to a more appropriate multilocus model (such that background selection can occur at multiple sites) suggests that, in regions of very low recombination rates, stationary levels of nucleotide diversity are primarily determined by hitchhiking, whereas in regions of high recombination, background selection is the dominant force. The implications of these results on the identification and estimation of the relevant parameters of the model are discussed.     

Expression of genetic and environmental variation during ageing

Summary To test for different gene activity during ageing, an experiment was set up to determine whether or not genetic variation and genetic correlations between fitness traits at different ages change in a systematic way through time. Additive genetic and environmental variance components as well as genetic correlations between different age periods were calculated for the fitness trait number of adult offspring in a population of Drosophila melanogaster. Genetic correlations between age periods were all positive and, hence, did not support the theory postulating that genes with beneficial effects on early fitness have pleiotropic unfavourable effects on late fitness. The environmental variation as well as the additive genetic variance showed a clear increase with age. The increase of environmental variation is probably a result of the individuals' increasing difficulties in coping with environmental stress due to physiological deterioration with age. Increased additive genetic variation may be explained by more and more genes being turned on with age. Alternatively, it could be caused by accumulation of deleterious mutations with different effects and may reflect the individuals' capacity of DNA repair.     

Expression of genetic and environmental variation during ageing

Summary A selection experiment with Drosophila melanogaster was carried out to test some theories of ageing by calculating genetic parameters for a reproductive fitness trait at different ages. Successful selection for increased lifespan showed that longevity is a trait under genetic control. Positive genetic correlations between early and late fitness were found. These results do not support the pleiotropy theory of ageing which predicts a negative genetic correlation. Both environmental and additive genetic variation clearly increased with age. Increased environmental variation probably reflects the individuals' difficulties in coping with environmental stress. The increase in additive genetic variation supports the mutation accumulation theory of ageing, as well as other theories that postulate increased additive genetic variation with age.     

Trypanosoma cruzi: H2 complex and genetic background influence on the humoral immune response against epimastigotes

Using A.SW, A.CA, B10.S and B10.M congenic mouse strains, we measured the IgG specific humoral immune responses against sonicated and live Trypanosoma cruzi epimastigotes. Genes located in the A background (A.SW and A.CA strains) mediate higher IgG responses against the parasite antigenic complexes than those located in the B background (strains B10.S and B10.M), regardless of the H2 haplotypes. Thus, non H2 genetic elements seem to be more important in determining differences in the total IgG immune response against T. cruzi. Whether a detectable H2 effect, in favor of the H2(s) haplotype, occurred in the A or B background, was contingent on the immunisation protocol used. Thus, the H2(s) haplotype mediates a higher IgG response in the A background, if immunised with live epimastigotes, and in the B background against sonicated epimastigotes. Most likely this represents a complex sequence of events, controlled by non-MHC genes, involving antigen handling and processing and depending on the physical form of antigen delivery.     

Finding the molecular basis of complex genetic variation in humans and mice

I survey the state of the art in complex trait analysis, including the use of new experimental and computational technologies and resources becoming available, and the challenges facing us. I also discuss how the prospects of rodent model systems compare with association mapping in humans.     

IGF2BP2 genetic variation and type 2 diabetes: a global meta-analysis

Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is involved in the stimulation of insulin action. Polymorphisms in the IGF2BP2 gene have been analyzed in numerous studies to assess the type 2 diabetes (T2D) risk attributed to these variants, but results are conflicting. To better understand the effect of rs4402960 polymorphism on T2D risk, we performed a comprehensive meta-analysis that included 35 published studies involving 70,261 cases and 100,567 controls. The relatively infrequent T variant was significantly associated with T2D with a per-allele odds ratio (OR) of 1.14 (95% confidence interval (CI): 1.12-1.16; p<10(-5)). Significant results were also observed for heterozygous (OR=1.17, 95% CI: 1.14-1.20; p<10(-5)) and homozygous (OR=1.23, 95% CI: 1.16-1.30; p<10(-5)) compared with wild type. In the subgroup analysis by ethnicity, significantly increased risks were found in East Asian, Caucasian and Indian populations. However, no significant associations were detected among other ethnicities. In the stratified analysis according to sample size, diagnostic criterion, mean body mass index, and age of cases significantly increased risks for the polymorphism were found in all genetic models. In conclusion, this meta-analysis suggests that rs4402960 polymorphism in IGF2BP2 is associated with elevated T2D risk, but these associations vary in different ethnic populations.     

Leaf shape evolution has a similar genetic architecture in three edaphic specialists within the Mimulus guttatus species complex

Background and Aims The genetic basis of leaf shape has long interested botanists because leaf shape varies extensively across the plant kingdom and this variation is probably adaptive. However, knowledge of the genetic architecture of leaf shape variation in natural populations remains limited. This study examined the genetic architecture of leaf shape diversification among three edaphic specialists in the Mimulus guttatus species complex. Lobed and narrow leaves have evolved from the entire, round leaves of M. guttatus in M. laciniatus, M. nudatus and a polymorphic serpentine M. guttatus population (M2L).Methods Bulk segregant analysis and next-generation sequencing were used to map quantitative trait loci (QTLs) that underlie leaf shape in an M. laciniatus × M. guttatus F₂ population. To determine whether the same QTLs contribute to leaf shape variation in M. nudatus and M2L, F₂s from M. guttatus × M. nudatus and lobed M2L × unlobed M. guttatus crosses were genotyped at QTLs from the bulk segregant analysis.Key Results Narrow and lobed leaf shapes in M. laciniatus, M. nudatus and M. guttatus are controlled by overlapping genetic regions. Several promising leaf shape candidate genes were found under each QTL.Conclusions The evolution of divergent leaf shape has taken place multiple times in the M. guttatus species complex and is associated with the occupation of dry, rocky environments. The genetic architecture of elongated and lobed leaves is similar across three species in this group. This may indicate that parallel genetic evolution from standing variation or new mutations is responsible for the putatively adaptive leaf shape variation in Mimulus.     

Characterization, chromosomal localization, and genetic variation of the porcine heart fatty acid-binding protein gene

The purpose of this study was to detect genetic variation in the porcine H-FABP gene, a candidate gene for meat quality traits in pigs. Lambda phages containing the porcine H-FABP gene were isolated by plaque hybridization with human H-FABP cDNA. The coding and flanking intronic sequences of the porcine H-FABP gene were determined as well as 1.6 kb of the 5′ upstream region. The various potential regulatory sequences in this region are in accordance with the function and expression of the protein in muscle and mammary tissue. Furthermore, comparison with the homolog region of the mouse identified a highly conserved 13-bp element (CTTCCT [A/C] TTTCGG) that may be involved in regulation of expression. The porcine H-FABP gene was localized on Chromosome (Chr) 6 by porcine sequence-specific PCR on DNA from a pig/rodent cell hybrid panel. In addition, part of the H-FABP gene was screened for genetic variation by PCR-RFLP analysis. Three PCR-RFLPs were detected, one in the upstream region (HinfI) and two in the second intron (HaeIII and MspI). In most pig breeds the corresponding alleles have a variable distribution, possibly a consequence of selective breeding. This genetic variation will enable us to investigate the role of the H-FABP locus in porcine production and meat quality traits. Received: 22 August 1996 / Accepted: 3 January 1997     

Natural isolates of Saccharomyces cerevisiae display complex genetic variation in sporulation efficiency

Sporulation is a well-studied process executed with varying efficiency by diverse yeast strains. We developed a high-throughput method to quantify yeast sporulation efficiency and used this technique to analyze a line cross between a high-efficiency oak tree isolate and a low-efficiency wine strain. We find that natural variation in sporulation efficiency mirrors natural variation in higher eukaryotes: it shows divergence between isolated populations, arises from loci of major effect, and exhibits epistasis. We show that the lower sporulation efficiency of the wine strain results from a failure to initiate sporulation, rather than from slower kinetics of meiosis and spore formation. The two strains differentially regulate many genes involved in aerobic respiration, an essential pathway for sporulation, such that the oak tree strain appears better poised to generate energy from this pathway. We also report that a polymorphism in RME1 that affects sporulation efficiency in laboratory strains also cosegregates with significant phenotypic differences in our cross of natural isolates. These results lay the groundwork for the study of variation in sporulation efficiency among natural isolates of yeast.     

The influence of genetic background on spontaneous and genetically engineered mouse models of complex diseases

In recent years, the use of genetically altered mice as models of complex human disease has revolutionized biomedical research into the genetics of disease pathogenesis and potential therapeutic interventions. Whether a mouse expresses a spontaneous or induced mutation, it is critical to remember that the observed phenotype is not always the direct result of the genetic alteration. The author points out the importance of considering the genetic background of the strain used to create these important models.     

Reduction in the E2k subunit of the alpha-ketoglutarate dehydrogenase complex has effects independent of complex activity

The activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC) declines in brains of patients with several neurodegenerative diseases. KGDHC consists of multiple copies of E1k, E2k, and E3. E1k and E2k are unique to KGDHC and may have functions independent of the complex. The present study tested the consequences of different levels of diminished E2k mRNA on protein levels of the subunits, KGDHC activity, and physiological responses. Human embryonic kidney cells were stably transfected with an E2k sense or antisense expression vector. Sense control (E2k-mRNA-100) was compared with two clones in which the mRNA was reduced to 67% of control (E2k-mRNA-67) or to 30% of control (E2k-mRNA-30). The levels of the E2k protein in clones paralleled the reduction in mRNA, and E3 proteins were unaltered. Unexpectedly, the clone with the greatest reduction in E2k protein (E2k-mRNA-30) had a 40% increase in E1k protein. The activity of the complex was only 52% of normal in E2k-mRNA-67 clone, but was near normal (90%) in E2k-mRNA-30 clone. Subsequent experiments tested whether the physiological consequences of a reduction in E2k mRNA correlated more closely to E2k protein or to KGDHC activity. Growth rate, increased DCF-detectable reactive oxygen species, and cell death in response to added oxidant were proportional to E2k proteins, but not complex activity. These results were not predicted because subunits unique to KGDHC have never been manipulated in mammalian cells. These results suggest that in addition to its essential role in metabolism, the E2k component of KGDHC may have other novel roles.