Mendelian Traits Research Articles

Heterozygous Mutations in DNA Repair Genes and Hereditary Breast Cancer: A Question of Power

Heterozygous Mutations in DNA Repair Genes and Hereditary Breast Cancer: A Question of Power

The effect of enterotoxigenic Escherichia coli F4ab,ac on early-weaned piglets: A gene expression study

Diarrhoea in neonatal and early-weaned piglets due to enterotoxigenic Escherichia coli-F4 (ETEC-F4) is an important problem in the pig farming industry. There is substantial evidence for a genetic basis for susceptibility to ETEC-F4 since not all pigs suffer from diarrhoea after an ETEC-F4 infection. A region on SSC13 has been found to be in close linkage to the susceptibility of piglets for ETEC-F4ab,ac. Potential candidate genes on SSC13 have been examined and although some polymorphisms were found to be in linkage disequilibrium with the phenotype, the causative mutation has not yet been found. In this study we are looking at the expression of porcine genes in relation to ETEC-F4ab,ac. With the aid of the Affymetrix GeneChip Porcine Genome Array we were able to find differentially expressed genes between ETEC-F4ab,ac receptor positive (Fab,acR+) piglets without diarrhoea and F4ab,acR+ piglets with diarrhoea or F4ab,acR− animals. Since the susceptibility to ETEC-F4ab,ac was described as a Mendelian trait, it is not so surprisingly that only two differentially expressed genes, transferrin receptor (TFRC) and trefoil factor 1 (TFF1), came out of the analysis. Although both genes could pass for functional candidate genes only TFRC also mapped to the region on SSC13 associated with susceptibility for ETEC-F4, which makes TFRC a positional functional candidate gene. Validation by qRT-PCR confirmed the differential expression of TFRC and TFF1. In piglets without diarrhoea, the expression of both genes was higher in F4ab,acR+ than in F4ab,acR− piglets. Similarly, TFRC and TFF1 expression in F4ab,acR+ piglets without diarrhoea was also higher than in F4ab,acR+ piglets with diarrhoea. Consequently, although both genes might not play a role as receptor for F4 fimbriae, they could be of great importance during an ETEC-F4 outbreak. An upregulation of TFRC can be a consequence of the piglets ability to raise an effective immune response. An elevation of TFF1, a protein involved in mucin formation, may also affect the piglet's capability to cope with ETEC bacteria, rather than being a receptor for its fimbriae.

Heuristic Methods for Finding Pathogenic Variants in Gene Coding Sequences

These are exciting times, with a plethora of new technologies that are expediting discovery of the genetic underpinnings of human disease. Comprehensive resequencing of the human genome is now feasible and affordable, allowing each person's entire genetic makeup to be revealed. The major focus of

The lavender plumage colour in Japanese quail is associated with a complex mutation in the region of MLPH that is related to differences in growth, feed consumption and body temperature

BackgroundThe lavender phenotype in quail is a dilution of both eumelanin and phaeomelanin in feathers that produces a blue-grey colour on a wild-type feather pattern background. It has been previously demonstrated by intergeneric hybridization that the lavender mutation in quail is homologous to the same phenotype in chicken, which is caused by a single base-pair change in exon 1 of MLPH.ResultsIn this study, we have shown that a mutation of MLPH is also associated with feather colour dilution in quail, but that the mutational event is extremely different. In this species, the lavender phenotype is associated with a non-lethal complex mutation involving three consecutive overlapping chromosomal changes (two inversions and one deletion) that have consequences on the genomic organization of four genes (MLPH and the neighbouring PRLH, RAB17 and LRRFIP1). The deletion of PRLH has no effect on the level of circulating prolactin. Lavender birds have lighter body weight, lower body temperature and increased feed consumption and residual feed intake than wild-type plumage quail, indicating that this complex mutation is affecting the metabolism and the regulation of homeothermy.ConclusionsAn extensive overlapping chromosome rearrangement was associated with a non-pathological Mendelian trait and minor, non deleterious effects in the lavender Japanese quail which is a natural knockout for PRLH.

Systems Genetics of Metabolism: The Use of the BXD Murine Reference Panel for Multiscalar Integration of Traits

Metabolic homeostasis is achieved by complex molecular and cellular networks that differ significantly among individuals and are difficult to model with genetically engineered lines of mice optimized to study single gene function. Here, we systematically acquired metabolic phenotypes by using the EUMODIC EMPReSS protocols across a large panel of isogenic but diverse strains of mice (BXD type) to study the genetic control of metabolism. We generated and analyzed 140 classical phenotypes and deposited these in an open-access web service for systems genetics (www.genenetwork.org). Heritability, influence of sex, and genetic modifiers of traits were examined singly and jointly by using quantitative-trait locus (QTL) and expression QTL-mapping methods. Traits and networks were linked to loci encompassing both known variants and novel candidate genes, including alkaline phosphatase (ALPL), here linked to hypophosphatasia. The assembled and curated phenotypes provide key resources and exemplars that can be used to dissect complex metabolic traits and disorders.

Higher Genetic Threshold for Progressive Adolescent Idiopathic Scoliosis in Male Individuals

Adolescent idiopathic scoliosis (AIS) affects up to 3% of children worldwide. It has been known for many decades that the female-to-male ratio is about 2:1 for minor curves whereas the ratio increases with increasing curve severity, reaching about 10:1 for curves of >30°. The molecular mechanisms that account for the predominance of females in the progressive and severe forms of AIS are currently unknown. Kruse et al. provide results of their quantitative genetic analyses of families with AIS that support a polygenic threshold model with sex dimorphism. Before commenting on the accompanying paper, there is a need to consider gene-variant effect sizes and the modes of inheritance of musculoskeletal and other disorders. In the past decade, rapid advances in genetic information and technology have enabled many new disease-associated genes to be identified in patients with skeletal dysplasias of unknown cause. The skeletal dysplasias include many hundreds of traits that usually follow Mendelian patterns of inheritance of single-gene disorders. In such traits, the gene-variant effect sizes are often large. Many studies have shown that very severe and lethal phenotypes, including those involving scoliosis, are often associated with very large single-gene-variant effect sizes. In such children, the adverse effects of the single gene mutations overwhelm any potentially beneficial effects of protective gene variants and environmental factors. However, families with milder Mendelian traits often have smaller single-gene-variant effect sizes and more marked variation in phenotypic severity. It is likely that the variation in severity of the phenotypes in such families is determined, at least in part, by the influence of other positive and negative gene variants and environmental factors. …

Mapping of crown gall resistance locus Rcg1 in grapevine

Agrobacteria are efficient plant pathogens. They are able to transform plant cells genetically resulting in abnormal cell proliferation. Cultivars of Vitis vinifera are highly susceptible to many virulent Agrobacterium strains but certain wild Vitis species, including Vitis amurensis have resistant genotypes. Studies of the molecular background of such natural resistance are of special importance, not only for practical benefits in agricultural practice but also for understanding the role of plant genes in the transformation process. Earlier, crown gall resistance from V. amurensis was introgressed into V. vinifera through interspecific breeding and it was shown to be inherited as a single and dominant Mendelian trait. To develop this research further, towards understanding underlying molecular mechanisms, a mapping population was established, and resistance-coupled molecular DNA markers were identified by three different approaches. First, RAPD makers linked to the resistance locus (Rcg1) were identified, and on the basis of their DNA sequences, we developed resistance-coupled SCAR markers. However, localization of these markers in the grapevine genome sequence failed due to their similarity to many repetitive regions. Next, using SSR markers of the grapevine reference linkage map, location of the resistance locus was established on linkage group 15 (LG15). Finally, this position was supported further by developing new chromosome-specific markers and by the construction of the genetic map of the region including nine loci in 29.1 cM. Our results show that the closest marker is located 3.3 cM from the Rcg1 locus that may correspond to 576 kb.

Spatially and temporally varying selection on intrapopulation quantitative trait loci for a life history trade‐off in Mimulus guttatus

AbstractWhy do populations remain genetically variable despite strong continuous natural selection? Mutation reconstitutes variation eliminated by selection and genetic drift, but theoretical and experimental studies each suggest that mutation‐selection balance insufficient to explain extant genetic variation in most complex traits. The alternative hypothesis of balancing selection, wherein selection maintains genetic variation, is an aggregate of multiple mechanisms (spatial and temporal heterogeneity in selection, frequency‐dependent selection, antagonistic pleiotropy, etc.). Most of these mechanisms have been demonstrated for Mendelian traits, but there is little comparable data for loci affecting quantitative characters. Here, we report a 3‐year field study of selection on intrapopulation quantitative trait loci (QTL) of flower size, a highly polygenic trait in Mimulus guttatus. The QTL exhibit antagonistic pleiotropy: alleles that increase flower size, reduce viability, but increase fecundity. The magnitude and direction of selection fluctuates yearly and on a spatial scale of metres. This study provides direct evidence of balancing selection mechanisms on QTL of an ecologically relevant trait.

A century of poultry genetics

The 20th Century saw an astonishing advance in our understanding of genetics and the scientific basis of the genetic improvement of farm animals. The application of genetic principles to chickens in the 1950s and 1960s led to a rapid change in the productivity and efficiency of laying hens and broiler chickens, turkeys and ducks. Subsequently, the application of increasingly powerful computers and sophisticated mathematical algorithms has increased the range of traits that could be successfully incorporated into breeding programs. Random sample tests of the performance of laying hens enjoyed a period of popularity and more recently the few remaining tests included husbandry systems in addition to strain evaluation. Characterisation of avian blood groups has led to the identification of the B21 haplotype that confers resistance to Marek's disease and to selection for this locus in commercial lines. The decade following the millennium saw the publication of the genome sequence of the chicken and the identification of millions of single nucleotide polymorphisms that, coupled with technological advances, made the application of whole genome selection practical in poultry. In parallel, the molecular basis for some Mendelian traits described a century ago is now being deciphered. Similar technologies have been applied to study genetic diversity in chickens and have provided insights into the evolution and domestication of chicken breeds. Finally, in this review, the recent development of the European Poultry Genetics Symposia coordinated by Working Group 3 ‘Genetics and Breeding’ that was based on combining the British Poultry Breeders Round Table and AVIAGEN from West and Eastern Europe, is discussed.

Preliminary identification of genetic mechanism of shank color in game chicken

This study aimed to explore a simple way to identify the genetic mechanism of shank color in chicken and provide an on-the-spot evaluation method for the trait without genealogy records. The shank color of 202 parental mating combinations and 489 offsprings were observed in Zhongyuan Game chicken and Snyder genetic ratios were calculated. The results showed that the cyan shank was dominant compared to the livid shank in Zhongyuan Game chicken, which was coincident with the characteristic of Mendelian trait in autosome. We concluded that Snyder genetic ratio was an effective way to identify the genetic mechanism of complex genetic trait. Key words: Chicken, shank color, Snyder, genetic mechanism.

Resolving the variable genome and epigenome in human disease

The individual human genome and epigenome are being defined at unprecedented resolution by current advances in sequencing technologies with important implications for human disease. This review uses examples relevant to clinical practice to illustrate the functional consequences of genetic and epigenetic variation. The insights gained from genome-wide association studies are described together with current efforts to understand the role of rare variants in common disease, set in the context of recent successes in Mendelian traits through the application of whole exome sequencing. The application of functional genomics to interrogate the genome and epigenome, build up an integrated picture of the regulatory genomic landscape and inform disease association studies is discussed, together with the role of expression quantitative trait mapping and analysis of allele-specific gene expression.

A Genome-Wide Association Study Identifies Two Novel Promising Candidate Genes Affecting Escherichia coli F4ab/F4ac Susceptibility in Swine

Enterotoxigenic Escherichia coli (ETEC) expressing F4 fimbria is the major pathogenic bacteria causing diarrhoea in neonatal and post-weaning piglets. Previous studies have revealed that the susceptibility to ETEC F4ab/F4ac is an autosomal Mendelian dominant trait and the loci controlling the F4ab/F4ac receptor are located on SSC13q41, between markers SW207 and S0283. To pinpoint these loci and further validate previous findings, we performed a genome-wide association study (GWAS) using a two generation family-based population, consisting of 301 piglets with phenotypes of susceptibility to ETEC F4ab/F4ac by the vitro adhesion test. The DNA of all piglets and their parents was genotyped using the Illumina PorcineSNP60 BeadChip, and 50,972 and 50,483 SNPs were available for F4ab and F4ac susceptibility, respectively, in the association analysis after quality control. In summary, 28 and 18 significant SNPs (p<0.05) were detected associated with F4ab and F4ac susceptibility respectively at genome-wide significance level. From these significant findings, two novel candidate genes, HEG1 and ITGB5, were firstly identified as the most promising genes underlying F4ab/F4ac susceptibility in swine according to their functions and positions. Our findings herein provide a novel evidence for unravelling genetic mechanism of diarrhoea risk in piglets.

Domesticated species form a treasure-trove for molecular characterization of Mendelian traits by exploiting the specific genetic structure of these species in across-breed genome wide association studies

Domesticated species have been important models for understanding phenotypic consequences of selection and genetics in the past 150 years. Among the most famous examples, is the work by Charles Darwin on the breeding of fancy pigeons that formed one of the pillars of his theory of evolution. Unknown to Darwin, around the time of publication of ‘On the Origin of Species’, Gregor Mendel conducted experiments on domesticated pea plants that would form the basis of the science of genetics. Domesticated animals and plants basically constitute the kinds of long-term genetic experiments researchers usually can only dream about. In fact, domestication and selection for specific phenotypes have resulted in thousands of generations of human-mediated selection and change, bringing about countless distinct phenotypes.

Analysis of genome-wide structure, diversity and fine mapping of Mendelian traits in traditional and village chickens

Extensive phenotypic variation is a common feature among village chickens found throughout much of the developing world, and in traditional chicken breeds that have been artificially selected for traits such as plumage variety. We present here an assessment of traditional and village chicken populations, for fine mapping of Mendelian traits using genome-wide single-nucleotide polymorphism (SNP) genotyping while providing information on their genetic structure and diversity. Bayesian clustering analysis reveals two main genetic backgrounds in traditional breeds, Kenyan, Ethiopian and Chilean village chickens. Analysis of linkage disequilibrium (LD) reveals useful LD (r(2) ≥ 0.3) in both traditional and village chickens at pairwise marker distances of ~10 Kb; while haplotype block analysis indicates a median block size of 11-12 Kb. Association mapping yielded refined mapping intervals for duplex comb (Gga 2:38.55-38.89 Mb) and rose comb (Gga 7:18.41-22.09 Mb) phenotypes in traditional breeds. Combined mapping information from traditional breeds and Chilean village chicken allows the oocyan phenotype to be fine mapped to two small regions (Gga 1:67.25-67.28 Mb, Gga 1:67.28-67.32 Mb) totalling ~75 Kb. Mapping the unmapped earlobe pigmentation phenotype supports previous findings that the trait is sex-linked and polygenic. A critical assessment of the number of SNPs required to map simple traits indicate that between 90 and 110K SNPs are required for full genome-wide analysis of haplotype block structure/ancestry, and for association mapping in both traditional and village chickens. Our results demonstrate the importance and uniqueness of phenotypic diversity and genetic structure of traditional chicken breeds for fine-scale mapping of Mendelian traits in the species, with village chicken populations providing further opportunities to enhance mapping resolutions.

Mendelian traits causing susceptibility to mucocutaneous fungal infections in human subjects

Mendelian traits causing susceptibility to mucocutaneous fungal infections in human subjects

Benign Familial Polycythaemia in a Young Male

Polycythaemia has been reported rarely as a familial condition. There is evidence to suggest transmission as a Mendelian dominant trait, but recessive inheritance has also been described. We present here a case of benign familial polycythaemia in a 25-year-old male with similar presentation in his family members. Our patient presented with reddish discolouration of the eyes, early satiety , weight loss and itching at intervals, for four years. An additional examination revealed red beefy tongue and Grade III clubbing. The importance of presenting this case lies in the fact that the prognosis appears to be good in these patients, but regular observation is necessary as Kiladjian and colleagues have mentioned that there is a risk of leukaemia, thrombosis and myelofibrosis in these patients later on, as the idiopathic erythrocytosis group contains a certain number of polycythaemia patients.

Bovine Genomics by James E. Womack

Bovine Genomics by James E. Womack

A Restricted Spectrum of Mutations in the SMAD4 Tumor-Suppressor Gene Underlies Myhre Syndrome

Myhre syndrome is a developmental disorder characterized by reduced growth, generalized muscular hypertrophy, facial dysmorphism, deafness, cognitive deficits, joint stiffness, and skeletal anomalies. Here, by performing exome sequencing of a single affected individual and coupling the results to a hypothesis-driven filtering strategy, we establish that heterozygous mutations in SMAD4, which encodes for a transducer mediating transforming growth factor β and bone morphogenetic protein signaling branches, underlie this rare Mendelian trait. Two recurrent de novo SMAD4 mutations were identified in eight unrelated subjects. Both mutations were missense changes altering Ile500 within the evolutionary conserved MAD homology 2 domain, a well known mutational hot spot in malignancies. Structural analyses suggest that the substituted residues are likely to perturb the binding properties of the mutant protein to signaling partners. Although SMAD4 has been established as a tumor suppressor gene somatically mutated in pancreatic, gastrointestinal, and skin cancers, and germline loss-of-function lesions and deletions of this gene have been documented to cause disorders that predispose individuals to gastrointestinal cancer and vascular dysplasias, the present report identifies a previously unrecognized class of mutations in the gene with profound impact on development and growth.

Finding Disease Variants in Mendelian Disorders By Using Sequence Data: Methods and Applications

Many sequencing studies are now underway to identify the genetic causes for both Mendelian and complex traits. Via exome-sequencing, genes harboring variants implicated in several Mendelian traits have already been identified. The underlying methodology in these studies is a multistep algorithm based on filtering variants identified in a small number of affected individuals and depends onwhether they are novel (not yet seen in public resources such as dbSNP), shared among affected individuals, and other external functional information on the variants. Although intuitive, these filter-based methods are nonoptimal and do not provide any measure of statistical uncertainty. We describe here a formal statistical approach that has several distinct advantages: (1) it provides fast computation of approximate p values for individual genes, (2) it adjusts for the background variation in each gene, (3) it allows for incorporation of functional or linkage-based information, and (4) it accommodates designs based on both affected relative pairs and unrelated affected individuals. We show via simulations that the proposed approach can be used in conjunction with the existing filter-based methods to achieve a substantially better ranking of a gene relevant for disease when compared to currently used filter-based approaches, this is especially so in the presence of disease locus heterogeneity. We revisit recent studies on three Mendeliandiseases and show that the proposed approach results in the implicated gene being ranked first in all studies, and approximate p values of 10(-6) for the Miller Syndrome gene, 1.0× 10(-4) for the Freeman-Sheldon Syndrome gene, and 3.5× 10(-5) for the Kabuki Syndrome gene.

Common and Rare Variants in Alcohol Dependence

c h a b c M any lines of evidence converge to show that genetics makes a substantial contribution to the risk for alcohol dependence, explaining about 60% of the variance. However, alcohol dependence is not a Mendelian trait with a simple pattern of inheritance, nor is it deterministic. It is a complex trait like most psychiatric diseases and other common diseases, with both genetic and environmental factors affecting risk. It is difficult to identify genes that affect the risk for complex diseases, but the huge impact of these diseases makes the attempt important. Early studies of alcohol dependence were limited to examining the role of small numbers of genetic variants in candidate genes, genes with a hypothesized role in alcoholism. Some were successful, particularly the identification of coding variations in ADH1B and ALDH2, genes that encode key enzymes in the metabolism of alcohol, with protective variants reducing risk by 2to 8-fold (1). Although other genes have also been implicated, no other variants with comparable effects are known. Some candidate genes have remained controversial. A strategy of linkage analysis followed up by genotyping of candidate genes within linked regions has also had success. A handful of genes have been confirmed to have variants affecting risk, including GABRA2 and ADH4 (2). Effect sizes are, however, small. Technological progress in genotyping single-nucleotide polymorphisms (SNPs) triggered genome-wide association studies (GWAS), which have the potential to discover genes not previously thought to be involved. After an initial striking success for agerelated macular degeneration (3), a wave of studies on many diseases was carried out with disappointing initial results: very few genes passed the accepted level of genome-wide significance, set at a high level of stringency because of the massive multiple testing these studies entail. Frequently, different studies on the same disease did not find the same results. Although this caused some to write off GWAS as a failure, a different take-home message began to emerge recently, as groups combined their data in metaanalyses. As the number of cases and controls grew dramatically, more and more genes have been identified in many diseases (4). It is clear that real effect sizes are much smaller than initially thought (or than calculated from the initial study, the so-called winners curse), so very large studies are needed to reliably detect them. The results of several initial GWAS on alcohol dependence and related traits, including one in this issue (5), fit this pattern. The studies differ in populations and ascertainment. A study of German male alcoholics with early onset of the disease, ascertained from hospitals, did not yield any SNPs at genome-wide significance, but follow-up of the top SNPs and selected candidate genes showed nominal significance, and a combined analysis reported that two SNPs on chromosome 2q35 (in strong linkage disequilibrium) reached genome-wide significance (6). Edenberg et al. (7) carried out a GWAS on subjects from the Collaborative Studies on the Genetics of Alcoholism (COGA) study, with no SNPs reaching ge-