Quantification of homozygosity in consanguineous individuals with autosomal recessive disease

Individuals born of consanguineous union have segments of their genomes that are homozygous as a result of inheriting identical ancestral genomic segments through both parents. One consequence of this is an increased incidence of recessive disease within these sibships. Theoretical calculations predict that 6% (1/16) of the genome of a child of first cousins will be homozygous and that the average homozygous segment will be 20 cM in size. We assessed whether these predictions held true in populations that have preferred consanguineous marriage for many generations. We found that in individuals with a recessive disease whose parents were first cousins, on average, 11% of their genomes were homozygous (n = 38; range 5%-20%), with each individual bearing 20 homozygous segments exceeding 3 cM (n = 38; range of number of homozygous segments 7-32), and that the size of the homozygous segment associated with recessive disease was 26 cM (n = 100; range 5-70 cM). These data imply that prolonged parental inbreeding has led to a background level of homozygosity increased approximately 5% over and above that predicted by simple models of consanguinity. This has important clinical and research implications.     

Structural and mechanistic investigations on Salmonella typhimurium acetate kinase (AckA): identification of a putative ligand binding pocket at the dimeric interface

Background

A large number of studies have been carried out to obtain amino acid propensities for ??-helices and ??-sheets. The obtained propensities for ??-helices are consistent with each other, and the pair-wise correlation coefficient is frequently high. On the other hand, the ??-sheet propensities obtained by several studies differed significantly, indicating that the context significantly affects ??-sheet propensity.

Results

We calculated amino acid propensities for ??-helices and ??-sheets for 39 and 24 protein folds, respectively, and addressed whether they correlate with the fold. The propensities were also calculated for exposed and buried sites, respectively. Results showed that ??-helix propensities do not differ significantly by fold, but ??-sheet propensities are diverse and depend on the fold. The propensities calculated for exposed sites and buried sites are similar for ??-helix, but such is not the case for the ??-sheet propensities. We also found some fold dependence on amino acid frequency in ??-strands. Folds with a high Ser, Thr and Asn content at exposed sites in ??-strands tend to have a low Leu, Ile, Glu, Lys and Arg content (correlation coefficient = ?0.90) and to have flat ??-sheets. At buried sites in ??-strands, the content of Tyr, Trp, Gln and Ser correlates negatively with the content of Val, Ile and Leu (correlation coefficient = ?0.93). "All-??" proteins tend to have a higher content of Tyr, Trp, Gln and Ser, whereas "??/??" proteins tend to have a higher content of Val, Ile and Leu.

Conclusions

The ??-helix propensities are similar for all folds and for exposed and buried residues. However, ??-sheet propensities calculated for exposed residues differ from those for buried residues, indicating that the exposed-residue fraction is one of the major factors governing amino acid composition in ??-strands. Furthermore, the correlations we detected suggest that amino acid composition is related to folding properties such as the twist of a ??-strand or association between two ?? sheets.     

Lung eQTLs to Help Reveal the Molecular Underpinnings of Asthma

Genome-wide association studies (GWAS) have identified loci reproducibly associated with pulmonary diseases; however, the molecular mechanism underlying these associations are largely unknown. The objectives of this study were to discover genetic variants affecting gene expression in human lung tissue, to refine susceptibility loci for asthma identified in GWAS studies, and to use the genetics of gene expression and network analyses to find key molecular drivers of asthma. We performed a genome-wide search for expression quantitative trait loci (eQTL) in 1,111 human lung samples. The lung eQTL dataset was then used to inform asthma genetic studies reported in the literature. The top ranked lung eQTLs were integrated with the GWAS on asthma reported by the GABRIEL consortium to generate a Bayesian gene expression network for discovery of novel molecular pathways underpinning asthma. We detected 17,178 cis- and 593 trans- lung eQTLs, which can be used to explore the functional consequences of loci associated with lung diseases and traits. Some strong eQTLs are also asthma susceptibility loci. For example, rs3859192 on chr17q21 is robustly associated with the mRNA levels of GSDMA (P = 3.55×10⁻¹⁵¹). The genetic-gene expression network identified the SOCS3 pathway as one of the key drivers of asthma. The eQTLs and gene networks identified in this study are powerful tools for elucidating the causal mechanisms underlying pulmonary disease. This data resource offers much-needed support to pinpoint the causal genes and characterize the molecular function of gene variants associated with lung diseases.     

Extent and consistency of linkage disequilibrium and identification of DNA markers for production and egg quality traits in commercial layer chicken populations

Background

The genome sequence and a high-density SNP map are now available for the chicken and can be used to identify genetic markers for use in marker-assisted selection (MAS). Effective MAS requires high linkage disequilibrium (LD) between markers and quantitative trait loci (QTL), and sustained marker-QTL LD over generations. This study used data from a 3,000 SNP panel to assess the level and consistency of LD between single nucleotide polymorphisms (SNPs) over consecutive years in two egg-layer chicken lines, and analyzed one line by two methods (SNP-wise association and genome-wise Bayesian analysis) to identify markers associated with egg-quality and egg-production phenotypes.

Results

The LD between markers pairs was high at short distances (r² > 0.2 at < 2 Mb) and remained high after one generation (correlations of 0.80 to 0.92 at < 5 Mb) in both lines. Single- and 3-SNP regression analyses using a mixed model with SNP as fixed effect resulted in 159 and 76 significant tests (P < 0.01), respectively, across 12 traits. A Bayesian analysis called BayesB, that fits all SNPs simultaneously as random effects and uses model averaging procedures, identified 33 SNPs that were included in the model >20% of the time (φ > 0.2) and an additional ten 3-SNP windows that had a sum of φ greater than 0.35. Generally, SNPs included in the Bayesian model also had a small P-value in the 1-SNP analyses.

Conclusion

High LD correlations between markers at short distances across two generations indicate that such markers will retain high LD with linked QTL and be effective for MAS. The different association analysis methods used provided consistent results. Multiple single SNPs and 3-SNP windows were significantly associated with egg-related traits, providing genomic positions of QTL that can be useful for both MAS and to identify causal mutations.

     

Effects of Hunting on Response Behaviors of Wild Reindeer

ABSTRACT Because wild reindeer (Rangifer tarandus) are hunted in southern Norway, reindeer may perceive all recreationists as threats. Potential adverse effects of hunting on reindeer behavior may be exacerbated by other forms of recreation because the number of skiers and hikers in areas inhabited by reindeer has also increased. The Norefjell-Reinsjøfjell wild reindeer area is used extensively for recreation and tourism. Reindeer hunting was introduced in the area in 1992, and harvest rate has been stable at about 38% of winter herd size. We recorded behavioral responses of reindeer to a person approaching directly on foot or skis during 1992 and again in 2002–2006. Compared to 1992, flight-initiation distance increased and fewer groups assessed the observer before taking flight during 2002–2006. In winter, when reindeer are usually comparably more vigilant than in other seasons, flight-initiation distance increased from only 60 m to 115 m and escape distance decreased from 400 m to 210 m. Neither alert distance, calf carcass weights (23.6 ± 0.7 [SE] kg to 22.4 ± 0.2 kg), nor reindeer herd size (661 ± 73 to 579 ± 15) changed during the 15 years of our study. Reindeer appeared to habituate to the observer because they initiated flight at shorter distances as the number of approaches on the same day increased. In Norefjell-Reinsjøfjell, encounters with a person on foot or skis did not result in behavioral responses likely to entail substantial energy costs for reindeer; therefore, hunting at current levels appears compatible with other recreational activities.     

The Simulium vernum group (Diptera: Simuliidae) in Europe: multiple character sets for assessing species status

The value of using characters from multiple sources – chromosomes, ecology, gene sequences, and morphology – to evaluate the species status of closely related black flies is demonstrated for three European members of the Simulium vernum group: Simulium crenobium (Knoz, 1961), Simulium juxtacrenobium Bass & Brockhouse, 1990, and Simulium vernum s.s. Macquart, 1826. Simulium juxtacrenobium is a chromosomally, molecularly, and morphologically distinct species that diverged from S. crenobium and S. vernum s.s. about 2 Mya. It is specialized for intermittent streams, is univoltine, and is recorded for the first time from northern Europe, based on collections from Finland and Sweden, representing a range extension of about 1800 km. In contrast, S. crenobium, although confirmed as a distinct species, differs from S. vernum s.s. by only a few larval and chromosomal characters, and by a breeding habitat restricted to mountain spring brooks. Whereas all four character sets independently support the specific distinctness of S. juxtacrenobium and S. vernum s.s., multiple character sets are required to establish the specific validity of S. crenobium.     

Molecular pathogenesis of autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is one of the commonest inherited human disorders yet remains relatively unknown to the wider medical, scientific and public audience. ADPKD is characterised by the development of bilateral enlarged kidneys containing multiple fluid-filled cysts and is a leading cause of end-stage renal failure (ESRF). ADPKD is caused by mutations in two genes: PKD1 and PKD2. The protein products of the PKD genes, polycystin-1 and polycystin-2, form a calcium-regulated, calcium-permeable ion channel. The polycystin complex is implicated in regulation of the cell cycle via multiple signal transduction pathways as well as the mechanosensory function of the renal primary cilium, an enigmatic cellular organelle whose role in normal physiology is still poorly understood. Defects in cilial function are now documented in several other human diseases including autosomal recessive polycystic kidney disease, nephronophthisis, Bardet-Biedl syndrome and many animal models of polycystic kidney disease. Therapeutic trials in these animal models of polycystic kidney disease have identified several promising drugs that ameliorate disease severity. However, elucidation of the function of the polycystins and the primary cilium will have a major impact on our understanding of renal cystic diseases and will create exciting new opportunities for the design of disease-specific therapies.