Larger genetic differences within africans than between Africans and Eurasians.

The worldwide pattern of single nucleotide polymorphism (SNP) variation is of great interest to human geneticists, population geneticists, and evolutionists, but remains incompletely understood. We studied the pattern in noncoding regions, because they are less affected by natural selection than are coding regions. Thus, it can reflect better the history of human evolution and can serve as a baseline for understanding the maintenance of SNPs in human populations. We sequenced 50 noncoding DNA segments each approximately 500 bp long in 10 Africans, 10 Europeans, and 10 Asians. An analysis of the data suggests that the sampling scheme is adequate for our purpose. The average nucleotide diversity (pi) for the 50 segments is only 0.061% +/- 0.010% among Asians and 0.064% +/- 0.011% among Europeans but almost twice as high (0.115% +/- 0.016%) among Africans. The African diversity estimate is even higher than that between Africans and Eurasians (0.096% +/- 0.012%). From available data for noncoding autosomal regions (total length = 47,038 bp) and X-linked regions (47,421 bp), we estimated the pi-values for autosomal regions to be 0.105, 0.070, 0.069, and 0.097% for Africans, Asians, Europeans, and between Africans and Eurasians, and the corresponding values for X-linked regions to be 0.088, 0.042, 0.053, and 0.082%. Thus, Africans differ from one another slightly more than from Eurasians, and the genetic diversity in Eurasians is largely a subset of that in Africans, supporting the out of Africa model of human evolution. Clearly, one must specify the geographic origins of the individuals sampled when studying pi or SNP density.

Genealogy and genes: tracing the founding fathers of Tristan da Cunha.

The island population of Tristan da Cunha has a well-documented genealogy that dates to its first permanent settlement in 1816. The current population is thought to have descended from only seven females and eight males. Today, there are seven family names in use, corresponding to the number of founding fathers with present-day male descendents. Y chromosome polymorphisms have previously been shown to be reliable tools for tracing patrilineal genealogies. Here, we studied Y chromosome polymorphisms in a sample from Tristan da Cunha together with genealogical records to (i) infer the haplotypes of the seven founders and (ii) test if the Y chromosome transmission is consistent with the documented patrilineal history of the island community. We observed nine Y chromosome haplotypes of which seven could be traced to the known ancestors. Of the two additional lineages, one probably evolved from a founder haplotype due to a single-step microsatellite mutation, while the other had an obvious non-island origin. Its introduction, however, is not reflected in the records. Four more instances of non-paternity were identified, with the "new" chromosomes matching other island haplotypes. The Y chromosome data presented here question the validity of some of the genealogical documentation and emphasise the value of genetic studies in tracing ancestry.

DNA polymorphism and selection at the melanocortin-1 receptor gene in normally pigmented southern African individuals.

Skin pigmentation is a polygenic multifactorial trait determined by the cumulative effects of multiple genetic variants and environmental factors. Melanocortin-1 receptor (MC1R) is one of the genes involved in pigmentation, and has been implicated in the red hair and pale skin phenotype in human Caucasoid individuals. The present study was undertaken to identify variation at the MC1R locus in normally pigmented individuals in two African populations, sub-Saharan Negroids (22 unrelated individuals) and the San (17 unrelated individuals). The study showed considerable MC1R gene sequence variation with the detection of eight synonymous and three nonsynonymous mutations. This is the first report of nonsynonymous mutations in African individuals in the MC1R gene: L99I was found in a single San individual, S47I was detected in a single Negroid individual, and F196L was detected in five Negroid individuals (5/44; 0.11). The functional significance of these mutations is not known. Three of the eight synonymous mutations found, L106L (CTG --> CTA), F300F (TTC --> TTT), and T314T (ACA --> ACG) (also known as A942G), have been reported previously. T314T was the only variant that showed a significant difference between the Negroid and San populations (0.477 and 0.059, respectively; P = 1.6 x 10(-5)). Its low frequency in the San may be the result of random genetic drift in a population of small size, or selection. Several tests of neutrality of the MC1R coding region in these and other African populations were significant, suggesting that purifying selection (functional constraint) had occurred at this gene locus in Africans. This demonstrates that although some nonsynonymous MC1R mutations are tolerated in individuals with dark skin, this gene has likely played a significant role in the maintenance of dark pigmentation in Africans and normal pigment variation in non-African populations.

The Steve Biko affair: a case study in medical ethics.

Steve Biko died in detention in South Africa in 1977. Critical ethical issues are raised both by the conduct of the doctors responsible for Biko's care and by the subsequent response of the medical profession as a whole. Because those issues are relevant to all healthcare professionals everywhere, the Biko affair provides a useful case study in medical ethics. We discuss the case in this article, describing how we use it in our teaching.

Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1).

Lipoid proteinosis (LP), also known as hyalinosis cutis et mucosae or Urbach-Wiethe disease (OMIM 247100) is a rare, autosomal recessive disorder typified by generalized thickening of skin, mucosae and certain viscera. Classical features include beaded eyelid papules and laryngeal infiltration leading to hoarseness. Histologically, there is widespread deposition of hyaline (glycoprotein) material and disruption/reduplication of basement membrane. The aetiology of LP is currently unknown. Using DNA from three affected siblings in a consanguineous Saudi Arabian family we performed genome-wide linkage and mapped the disorder to 1q21 (marker D1S498) with a two-point LOD score of 3.45 at theta = 0. A further 28 affected individuals from five other unrelated consanguineous family groups from different geographical regions also showed complete linkage and resulted in a maximum two-point LOD score of 21.85 at theta = 0. Using available markers in the interval between D1S442 and D1S305, the observed recombinants placed the gene in a 2.3 cM critical interval between D1S2344 and D1S2343 (Marshfield genetic map) corresponding to an approximately 6.5 Mb region on the UCSC physical map. Using a candidate gene approach (comparison of control versus LP gene expression in cultured fibroblasts) and subsequent direct sequencing of genomic DNA, we identified six different homozygous loss-of-function mutations in the extracellular matrix protein 1 gene (ECM1). Although the precise function of ECM1 is not known, our findings provide the first clinical indication of its relevance to skin adhesion, epidermal differentiation, wound healing, scarring, angiogenesis/angiopathy and basement membrane physiology, as well as defining the molecular basis of this inherited disorder.