Inclusion of genetically identical animals to a numerator relationship matrix and modification of its inverse

In the field of animal breeding, estimation of genetic parameters and prediction of breeding values are routinely conducted by analyzing quantitative traits. Using an animal model and including the direct inverse of a numerator relationship matrix (NRM) into a mixed model has made these analyses possible. However, a method including a genetically identical animal (GIA) in NRM if genetic relationships between pairs of GIAs are not perfect, is still lacking. Here, we describe a method to incorporate GIAs into NRM using a K matrix in which diagonal elements are set to 1.0, off-diagonal elements between pairs of GIAs to (1-x) and the other elements to 0, where x is a constant less than 0.05. The inverse of the K matrix is then calculated directly by a simple formula. Thus, the inverse of the NRM is calculated by the products of the lower triangular matrix that identifies the parents of each individual, its transpose matrix, the inverse of the K matrix and the inverse of diagonal matrix D, in which the diagonal elements comprise a number of known parents and their inbreeding coefficients. The computing method is adaptable to the analysis of a data set including pairs of GIAs with imperfect relationships

Genetic, environmental and stochastic factors in monozygotic twin discordance with a focus on epigenetic differences

PMCID: PMC3566971This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Genome-Wide Analysis of Copy Number Variation in Type 1 Diabetes

Type 1 diabetes (T1D) tends to cluster in families, suggesting there may be a genetic component predisposing to disease. However, a recent large-scale genome-wide association study concluded that identified genetic factors, single nucleotide polymorphisms, do not account for overall familiality. Another class of genetic variation is the amplification or deletion of >1 kilobase segments of the genome, also termed copy number variations (CNVs). We performed genome-wide CNV analysis on a cohort of 20 unrelated adults with T1D and a control (Ctrl) cohort of 20 subjects using the Affymetrix SNP Array 6.0 in combination with the Birdsuite copy number calling software. We identified 39 CNVs as enriched or depleted in T1D versus Ctrl. Additionally, we performed CNV analysis in a group of 10 monozygotic twin pairs discordant for T1D. Eleven of these 39 CNVs were also respectively enriched or depleted in the Twin cohort, suggesting that these variants may be involved in the development of islet autoimmunity, as the presently unaffected twin is at high risk for developing islet autoimmunity and T1D in his or her lifetime. These CNVs include a deletion on chromosome 6p21, near an HLA-DQ allele. CNVs were found that were both enriched or depleted in patients with or at high risk for developing T1D. These regions may represent genetic variants contributing to development of islet autoimmunity in T1D

The Causal Cascade to Multiple Sclerosis: A Model for MS Pathogenesis

BACKGROUND: MS pathogenesis seems to involve both genetic susceptibility and environmental risk factors. Three sequential factors are implicated in the environmental risk. The first acts near birth, the second acts during childhood, and the third acts long thereafter. Two candidate factors (vitamin D deficiency and Epstein-Barr viral infection) seem well suited to the first two environmental events. METHODOLOGY/PRINCIPAL FINDINGS: A mathematical Model for MS pathogenesis is developed, incorporating these environmental and genetic factors into a causal scheme that can explain some of the recent changes in MS-epidemiology (e.g., increasing disease prevalence, a changing sex-ratio, and regional variations in monozygotic twin concordance rates). CONCLUSIONS/SIGNIFICANCE: This Model suggests that genetic susceptibility is overwhelmingly the most important determinant of MS pathogenesis. Indeed, over 99% of individuals seem genetically incapable of developing MS, regardless of what environmental exposures they experience. Nevertheless, the contribution of specific genes to MS-susceptibility seems only modest. Thus, despite HLA DRB1*1501 being the most consistently identified genetic marker of MS-susceptibility (being present in over 50% of northern MS patient populations), only about 1% of individuals with this allele are even genetically susceptible to getting MS. Moreover, because genetic susceptibility seems so similar throughout North America and Europe, environmental differences principally determine the regional variations in disease characteristics. Additionally, despite 75% of MS-patients being women, men are 60% more likely to be genetically-susceptible than women. Also, men develop MS at lower levels of environmental exposure than women. Nevertheless, women are more responsive to the recent changes in environmental-exposure (whatever these have been). This explains both the changing sex-ratio and the increasing disease prevalence (which has increased by a minimum of 32% in Canada over the past 35 years). As noted, environmental risk seems to result from three sequential components of environmental exposure. The potential importance of this Model for MS pathogenesis is that, if correct, a therapeutic strategy, designed to interrupt one or more of these sequential factors, has the potential to markedly reduce or eliminate disease prevalence in the future

A Microhomology-Mediated Break-Induced Replication Model for the Origin of Human Copy Number Variation

Chromosome structural changes with nonrecurrent endpoints associated with genomic disorders offer windows into the mechanism of origin of copy number variation (CNV). A recent report of nonrecurrent duplications associated with Pelizaeus-Merzbacher disease identified three distinctive characteristics. First, the majority of events can be seen to be complex, showing discontinuous duplications mixed with deletions, inverted duplications, and triplications. Second, junctions at endpoints show microhomology of 2–5 base pairs (bp). Third, endpoints occur near pre-existing low copy repeats (LCRs). Using these observations and evidence from DNA repair in other organisms, we derive a model of microhomology-mediated break-induced replication (MMBIR) for the origin of CNV and, ultimately, of LCRs. We propose that breakage of replication forks in stressed cells that are deficient in homologous recombination induces an aberrant repair process with features of break-induced replication (BIR). Under these circumstances, single-strand 3′ tails from broken replication forks will anneal with microhomology on any single-stranded DNA nearby, priming low-processivity polymerization with multiple template switches generating complex rearrangements, and eventual re-establishment of processive replication

Growth hormone overexpression in the central nervous system results in hyperphagia-induced obesity associated with insulin resistance and dyslipidemia

It is well known that peripherally administered growth hormone (GH) results in decreased body fat mass. However, GH-deficient patients increase their food intake when substituted with GH, suggesting that GH also has an appetite stimulating effect. Transgenic mice with an overexpression of bovine GH in the central nervous system (CNS) were created to investigate the role of GH in CNS. This study shows that overexpression of GH in the CNS differentiates the effect of GH on body fat mass from that on appetite. The transgenic mice were not GH-deficient but were obese and showed increased food intake as well as increased hypothalamic expression of agouti-related protein and neuropeptide Y. GH also had an acute effect on food intake following intra-cerebroventricular injection of C57BL/6 mice. The transgenic mice were severely hyperinsulinemic and showed a marked hyperplasia of the islets of Langerhans. In addition, the transgenic mice displayed alterations in serum lipid and lipoprotein levels and hepatic gene expression. In conclusion, GH overexpression in the CNS results in hyperphagia-induced obesity indicating a dual effect of GH with a central stimulation of appetite and a peripheral lipolytic effect