Genetic mapping and developmental timing of transmission ratio distortion in a mouse interspecific backcross

<p>Abstract</p> <p>Background</p> <p>Transmission ratio distortion (TRD), defined as statistically significant deviation from expected 1:1 Mendelian ratios of allele inheritance, results in a reduction of the expected progeny of a given genotype. Since TRD is a common occurrence within interspecific crosses, a mouse interspecific backcross was used to genetically map regions showing TRD, and a developmental analysis was performed to identify the timing of allele loss.</p> <p>Results</p> <p>Three independent events of statistically significant deviation from the expected 50:50 Mendelian inheritance ratios were observed in an interspecific backcross between the <it>Mus musculus </it>A/J and the <it>Mus spretus </it>SPRET/EiJ inbred strains. At weaning <it>M. musculus </it>alleles are preferentially inherited on Chromosome (Chr) 7, while <it>M. spretus </it>alleles are preferentially inherited on Chrs 10 and 11. Furthermore, alleles on Chr 3 modify the TRD on Chr 11. All TRD loci detected at weaning were present in Mendelian ratios at mid-gestation and at birth.</p> <p>Conclusions</p> <p>Given that Mendelian ratios of inheritance are observed for Chr 7, 10 and 11 during development and at birth, the underlying causes for the interspecific TRD events are the differential post-natal survival of pups with specific genotypes. These results are consistent with the TRD mechanism being deviation from Mendelian inheritance rather than meiotic drive or segregation distortion.</p

Mapping Six New Susceptibility to Colon Cancer ( Scc ) Loci Using a Mouse Interspecific Backcross

Colorectal cancer (CRC) has a complex etiology resulting from the combination of multiple genetic and environmental factors, each with small effects. Interactions among susceptibility modifier loci make many of the loci difficult to detect in human genome-wide association studies. Previous analyses in mice have used classical inbred strains, which share large portions of their genomes due to common ancestry. Herein, we used an interspecific backcross between the Mus musculus strain A/J and the Mus spretus strain SPRET/EiJ to map 6 additional CRC modifier loci (Scc16-21) and 2 suggestive loci. Three loci modify the location of tumors along the proximal-distal axis of the colon. Six CRC modifiers previously mapped in intraspecific crosses were also replicated. This work confirms genetic models suggesting that CRC is caused by many small effect alleles and brings the catalog of reported CRC modifier loci to 23 spread across 13 chromosomes. Furthermore, this work provides the foundation for large population-level epistatic interaction tests to identify combinations of low effect alleles that may have large effects on CRC susceptibility

L'Angleterre

Eversley David edward charles. L'Angleterre. In: Bibliothèque de la Révolution de 1848, Tome 20, 1958. Le Choléra, la première épidémie du XIXe siècle

L'Angleterre

Eversley David edward charles. L'Angleterre. In: Bibliothèque de la Révolution de 1848, Tome 20, 1958. Le Choléra, la première épidémie du XIXe siècle

Rapid Elevation in CMPF May Act As a Tipping Point in Diabetes Development

Prediabetes, a state of mild glucose intolerance, can persist for years before a sudden decline in beta cell function and rapid deterioration to overt diabetes. The mechanism underlying this tipping point of beta cell dysfunction remains unknown. Here, the furan fatty acid metabolite CMPF was evaluated in a prospective cohort. Those who developed overt diabetes had a significant increase in CMPF over time, whereas prediabetics maintained chronically elevated levels, even up to 5 years before diagnosis. To evaluate the effect of increasing CMPF on diabetes progression, we used obese, insulin-resistant models of prediabetes. CMPF accelerated diabetes development by inducing metabolic remodeling, resulting in preferential utilization of fatty acids over glucose. This was associated with diminished glucose-stimulated insulin secretion, increased ROS formation, and accumulation of proinsulin, all characteristics of human diabetes. Thus, an increase in CMPF may represent the tipping point in diabetes development by accelerating beta cell dysfunction