Massively parallel sequencing of the mouse exome to accurately identify rare, induced mutations: an immediate source for thousands of new mouse models.

Accurate identification of sparse heterozygous single-nucleotide variants (SNVs) is a critical challenge for identifying the causative mutations in mouse genetic screens, human genetic diseases and cancer. When seeking to identify causal DNA variants that occur at such low rates, they are overwhelmed by false-positive calls that arise from a range of technical and biological sources. We describe a strategy using whole-exome capture, massively parallel DNA sequencing and computational analysis, which identifies with a low false-positive rate the majority of heterozygous and homozygous SNVs arising de novo with a frequency of one nucleotide substitution per megabase in progeny of N-ethyl-N-nitrosourea (ENU)-mutated C57BL/6j mice. We found that by applying a strategy of filtering raw SNV calls against known and platform-specific variants we could call true SNVs with a false-positive rate of 19.4 per cent and an estimated false-negative rate of 21.3 per cent. These error rates are small enough to enable calling a causative mutation from both homozygous and heterozygous candidate mutation lists with little or no further experimental validation. The efficacy of this approach is demonstrated by identifying the causative mutation in the Ptprc gene in a lymphocyte-deficient strain and in 11 other strains with immune disorders or obesity, without the need for meiotic mapping. Exome sequencing of first-generation mutant mice revealed hundreds of unphenotyped protein-changing mutations, 52 per cent of which are predicted to be deleterious, which now become available for breeding and experimental analysis. We show that exome sequencing data alone are sufficient to identify induced mutations. This approach transforms genetic screens in mice, establishes a general strategy for analysing rare DNA variants and opens up a large new source for experimental models of human disease.

Testing for AIDS: uses and abuses.

In response to the public outcry for mandatory testing for AIDS, this Article explores the major issues concerning the identification of persons with AIDS in society. The Article first studies testing procedures and the purposes behind them to determine if a call for mandatory testing of the general populace would better achieve society's objectives for identifying individuals with AIDS. Concluding that testing should not be required of the population as a whole, the Article then explores whether testing should be required of certain subpopulations which society perceives as likely to have or to spread the disease. In this context, too, the Article concludes that mandatory testing would be unwarranted, and that funds proposed for mandatory testing would be put to better use in education and universal precautions to prevent the further spread of AIDS.

Emotional disorder in XYY children: four case reports.

Four boys, from a group of fourteen with an XYY chromosome constitution identified by cytogenetic screening at birth, were referred for psychiatric treatment, age seven to nine years. Presenting symptoms included severe temper tantrums, stealing and enuresis, and they were diagnosed as having mild to severe emotional disorders. There were multiple factors of increased risk for psychiatric disturbance in their backgrounds nd there was evidence of reactive depression in all four boys. Treatment with individual and family psychotherapy, combined with antidepressant medication in two of the four children and special educational provisions in one, resulted in good short-term outcome comparable to that achieved in chromosomally normal boys.

A chromosome survey of a hospital for the mentally subnormal.

A cytogenetic survey of 756 resident, but otherwise unselected, mentally retarded patients in a Scottish hospital is reported. The karyotypes of all patients were examined using orcein-stained cells, and those found to be abnormal, other than those with standard trisomy 21, were further investigated using a banding technique. A total of 103 patients were found to have an abnormal chromosome complement, of whom 91 had Down's syndrome (including six with translocations), six had some other autosomal abnormality, and six had an abnormality of the sex chromosome complement, including two with an XXYY complement. Details of the clinical and cytogenetic features are presented.