Statistical method for testing the neutral mutation hypothesis by DNA polymorphism.

Current routine genotyping methods typically do not provide haplotype information, which is essential for many analyses of fine-scale molecular-genetics data. Haplotypes can be obtained, at considerable cost, experimentally or (partially) through genotyping of additional family members. Alternatively, a statistical method can be used to infer phase and to reconstruct haplotypes. We present a new statistical method, applicable to genotype data at linked loci from a population sample, that improves substantially on current algorithms; often, error rates are reduced by >50%, relative to its nearest competitor. Furthermore, our algorithm performs well in absolute terms, suggesting that reconstructing haplotypes experimentally or by genotyping additional family members may be an inefficient use of resources.

https://cseweb.ucsd.edu/classes/sp05/cse291-a/doc/phase.pdf

A new statistical method for haplotype reconstruction from population data.

Although DNA is the carrier of genetic information, it has limited chemical stability. Hydrolysis, oxidation and nonenzymatic methylation of DNA occur at significant rates in vivo, and are counteracted by specific DNA repair processes. The spontaneous decay of DNA is likely to be a major factor in mutagenesis, carcinogenesis and ageing, and also sets limits for the recovery of DNA fragments from fossils.

Instability and decay of the primary structure of DNA

The human genome contains many dispersed tandem-repetitive 'minisatellite' regions detected via a shared 10-15-base pair 'core' sequence similar to the generalized recombination signal (chi) of Escherichia coli. Many minisatellites are highly polymorphic due to allelic variation in repeat copy number in the minisatellite. A probe based on a tandem-repeat of the core sequence can detect many highly variable loci simultaneously and can provide an individual-specific DNA 'fingerprint' of general use in human genetic analysis.

/pdf/hypervariable-minisatellite-regions-in-human-dna-3e6is3j7he.pdf

Hypervariable 'minisatellite' regions in human DNA.

Interest in mapping the global distribution of malaria is motivated by a need to define populations at risk for appropriate resource allocation and to provide a robust framework for evaluating its global economic impact. Comparison of older and more recent malaria maps shows how the disease has been geographically restricted, but it remains entrenched in poor areas of the world with climates suitable for transmission. Here we provide an empirical approach to estimating the number of clinical events caused by Plasmodium falciparum worldwide, by using a combination of epidemiological, geographical and demographic data. We estimate that there were 515 (range 300-660) million episodes of clinical P. falciparum malaria in 2002. These global estimates are up to 50% higher than those reported by the World Health Organization (WHO) and 200% higher for areas outside Africa, reflecting the WHO's reliance upon passive national reporting for these countries. Without an informed understanding of the cartography of malaria risk, the global extent of clinical disease caused by P. falciparum will continue to be underestimated.

/pdf/the-global-distribution-of-clinical-episodes-of-plasmodium-20zeeiovaa.pdf

The global distribution of clinical episodes of Plasmodium falciparum malaria

Despite major advances in our understanding of the molecular pathology, pathophysiology, and control and management of the inherited disorders of haemoglobin, thousands of infants and children with these diseases are dying through lack of appropriate medical care. This problem will undoubtedly increase over the next 20 years because, as the result of a reduction in childhood mortality due to infection and malnutrition, more babies with haemoglobin disorders will survive to present for treatment. Although WHO and various voluntary agencies have tried to disseminate information about these diseases, they are rarely mentioned as being sufficiently important to be included in setting health care priorities for the future. It takes considerable time to establish expertise in developing programmes for the control and management of these conditions, and the lessons learned in developed countries will need to be transmitted to those countries in which they occur at a high frequency.

/pdf/inherited-haemoglobin-disorders-an-increasing-global-health-klmby5lk4p.pdf

Inherited haemoglobin disorders: an increasing global health problem.

World distribution of factor V Leiden

Authors and Contributors. Preface to the Fourth Edition. Preface to the First Edition. Acknowledgements. Part 1 Historical Background.1. Historical Perspectives: The Many and Diverse Routes to our Current Understanding of the Thalassaemia Syndromes. Part 2 The Biology of The Thalassaemias. 2. Human Haemoglobin 3. Thalassaemia: Classification and Relationship to Other Inherited Diseases of Haemoglobin.4. The Molecular Pathology of the Thalassaemias. 5. Pathophysiology of the Thalassaemias. 6. The World Distribution and Population Genetics of Thalassaemia. Part 3 Clinical Features of the Thalassaemias 7. The beta Thalassaemias.8. The delta beta and Related Thalassaemias 9. The beta and delta beta Thalassaemia in Association with Structural Haemoglobin Variants.10. Hereditary Persistence of Fetal Haemoglobin.11. The alpha Thalassaemias and Their Interactions with Structural Haemoglobin Variants. 12. Thalassaemia withmental retardation or Myelodysplasia. 13. Thalassaemia Intermedia. Part 4 Diagnosis and management of thalassaemia. 14. Avoidance and Population Control.15. Management and prognosis.16. Laboratory Diagnosis of the Thalassaemias. Part 5 The Future. References. Appendix. Index.

The thalassaemia syndromes

The thalassaemia syndromes.

A mutant allele of the beta-chemokine receptor gene CCR5 bearing a 32-basepair (bp) deletion (denoted delta ccr5) which prevents cell invasion by the primary transmitting strain of HIV-1 has recently been characterized. Homozygotes for the mutation are resistant to infection, even after repeated high-risk exposures, but this resistance appears not to be total, as isolated cases of HIV-positive deletion homozygotes are now emerging. The consequence of the heterozygous state is not clear, but it may delay the progression to AIDS in infected individuals. A gene frequency of approximately 10% was found for delta ccr5 in populations of European descent, but no mutant alleles were reported in indigenous non-European populations. As the total number of non-European samples surveyed was small in comparison with the Europeans the global distribution of this mutation is far from clear. We have devised a rapid PCR assay for delta ccr5 and used it to screen 3,342 individuals from a globally-distributed range of populations. We find that delta ccr5 is not confined to people of European descent but is found at frequencies of 2-5% throughout Europe, the Middle East and the Indian subcontinent (Fig. 1). Isolated occurrences are seen elsewhere throughout the world, but these most likely represent recent European gene flow into the indigenous populations. The inter-population differences in delta ccr5 frequency may influence the pattern of HIV transmission and so will need to be incorporated into future predictions of HIV levels.

John B. Clegg

Papers

Inherited haemoglobin disorders: an increasing global health problem.

World distribution of factor V Leiden

The thalassaemia syndromes

The thalassaemia syndromes.

Global distribution of the CCR5 gene 32-basepair deletion.