Audrey Lynn

A genome-wide linkage analysis investigating the determinants of blood pressure in whites and African Americans.

Evidence for genomic regions influencing systolic and diastolic blood pressure (BP) were assessed in a whole genome linkage analysis in 211 African American and 160 white families as part of the GenNet network of the National Heart, Lung and Blood Institute-sponsored Family Blood Pressure Program. Multipoint regression and variance components linkage methods were used to analyze 372 polymorphic markers. Statistically compelling evidence for linkage (P values .0057 and .00023, respectively) was found on chromosome 1. Our results support the idea that BP regulation is most likely governed by multiple genetic loci, each with a relatively weak effect on BP in the population at large.

Sex, Not Genotype, Determines Recombination Levels in Mice

Recombination, the precise physical breakage and rejoining of DNA between homologous chromosomes, plays a central role in mediating the orderly segregation of meiotic chromosomes in most eukaryotes. Despite its importance, the factors that control the number and placement of recombination events within a cell remain poorly defined. The rate of recombination exhibits remarkable species specificity, and, within a species, recombination is affected by the physical size of the chromosome, chromosomal location, proximity to other recombination events (i.e., chiasma interference), and, intriguingly, the sex of the transmitting parent. To distinguish between simple genetic and nongenetic explanations of sex-specific recombination differences in mammals, we compared recombination in meiocytes from XY sex-reversed and XO females with that in meiocytes from XX female and XY male mice. The rate and pattern of recombination in XY and XO oocytes were virtually identical to those in normal XX females, indicating that sex, not genotype, is the primary determinant of meiotic recombination patterns in mammals.

Autosomal dominant acute necrotizing encephalopathy maps to 2q12.1-2q13

In autosomal dominant acute necrotizing encephalopathy (ADANE), apparently healthy children develop necrotizing lesions in their thalami and brainstems in the course of febrile illnesses. We used DNA from affected subjects and obligate carriers to map ADANE to a 6.5Mb region on chromosome 2. Sequencing of four candidate genes in the interval (BCL2L11, ST6GalII, CHT1, and FLJ20019), involved in apoptosis, viral recognition, choline transport, and electron transport, showed no disease causing mutations.

Segregation analysis of microcephaly.

Microcephaly is a heterogeneous disorder with genetic and environmental causes. However, there is little information on what proportion of cases are caused by inherited susceptibility, or the mode of inheritance in familial cases. To address these questions, we have performed classical and complex segregation analyses for microcephaly on 2 sets of family data collected from genetic counseling clinics in Vancouver and Jerusalem. These samples consisted of 143 affected individuals in 127 families ascertained from Vancouver, and 101 affected individuals in 59 families ascertained from Jerusalem. The results of the segregation analyses for the Vancouver sample indicated that approximately half of all microcephaly cases were due to highly penetrant recessive mutant alleles, with the remainder being sporadic. Although a recessive model allowing for the occurrence of sporadic cases fit the data from Vancouver best, a dominant model could not be statistically rejected. The classical segregation analysis on the Jerusalem sample suggested that both a dominant model with 29% of the cases being sporadic and a purely recessive model provided adequate fit to the data. Although the complex segregation analysis of this sample indicated that a dominant model provided a more parsimonious explanation for the observed familial variation, a recessive model was only marginally rejected. It should be noted that in the Jerusalem sample, families tended to be ascertained in the genetic counseling clinic only after the birth of a second affected child. This could be a potential bias which could inflate the segregation ratio, thus giving the impression of dominant inheritance. Our analyses, while confirming the complex nature of the cause of microcephaly, indicate that it may be necessary to await the results of genetic linkage analysis before a definitive mode of inheritance can be determined.