Estimating individual genome-wide autozygosity is important both in the identification of recessive disease variants via homozygosity mapping and in the investigation of the effects of genome-wide homozygosity on traits of biomedical importance. Approaches have tended to involve either single-point estimates or rather complex multipoint methods of inferring individual autozygosity, all on the basis of limited marker data. Now, with the availability of high-density genome scans, a multipoint, observational method of estimating individual autozygosity is possible. Using data from a 300,000 SNP panel in 2618 individuals from two isolated and two more-cosmopolitan populations of European origin, we explore the potential of estimating individual autozygosity from data on runs of homozygosity (ROHs). Termed F(roh), this is defined as the proportion of the autosomal genome in runs of homozygosity above a specified length. Mean F(roh) distinguishes clearly between subpopulations classified in terms of grandparental endogamy and population size. With the use of good pedigree data for one of the populations (Orkney), F(roh) was found to correlate strongly with the inbreeding coefficient estimated from pedigrees (r = 0.86). Using pedigrees to identify individuals with no shared maternal and paternal ancestors in five, and probably at least ten, generations, we show that ROHs measuring up to 4 Mb are common in demonstrably outbred individuals. Given the stochastic variation in ROH number, length, and location and the fact that ROHs are important whether ancient or recent in origin, approaches such as this will provide a more useful description of genomic autozygosity than has hitherto been possible.

Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200-500 microM) compared with other mammals (3-120 microM). About 70% of daily urate disposal occurs via the kidneys, and in 5-25% of the human population, impaired renal excretion leads to hyperuricemia. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7-5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes.

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Mitochondrial HVS-I sequences from 10,365 subjects belonging to 56 populations/geographical regions of western Eurasia and northern Africa were first surveyed for the presence of the T-->C transition at nucleotide position 16298, a mutation which has previously been shown to characterize haplogroup V mtDNAs. All mtDNAs with this mutation were then screened for a number of diagnostic RFLP sites, revealing two major subsets of mtDNAs. One is haplogroup V proper, and the other has been termed "pre*V," since it predates V phylogenetically. The rather uncommon pre*V tends to be scattered throughout Europe (and northwestern Africa), whereas V attains two peaks of frequency: one situated in southwestern Europe and one in the Saami of northern Scandinavia. Geographical distributions and ages support the scenario that pre*V originated in Europe before the Last Glacial Maximum (LGM), whereas the more recently derived haplogroup V arose in a southwestern European refugium soon after the LGM. The arrival of V in eastern/central Europe, however, occurred much later, possibly with (post-)Neolithic contacts. The distribution of haplogroup V mtDNAs in modern European populations would thus, at least in part, reflect the pattern of postglacial human recolonization from that refugium, affecting even the Saami. Overall, the present study shows that the dissection of mtDNA variation into small and well-defined evolutionary units is an essential step in the identification of spatial frequency patterns. Mass screening of a few markers identified using complete mtDNA sequences promises to be an efficient strategy for inferring features of human prehistory.

A maximum parsimony tree of 21 complete mitochondrial DNA (mtDNA) sequences belonging to haplogroup X and the survey of the haplogroup-associated polymorphisms in 13,589 mtDNAs from Eurasia and Africa revealed that haplogroup X is subdivided into two major branches, here defined as "X1" and "X2." The first is restricted to the populations of North and East Africa and the Near East, whereas X2 encompasses all X mtDNAs from Europe, western and Central Asia, Siberia, and the great majority of the Near East, as well as some North African samples. Subhaplogroup X1 diversity indicates an early coalescence time, whereas X2 has apparently undergone a more recent population expansion in Eurasia, most likely around or after the last glacial maximum. It is notable that X2 includes the two complete Native American X sequences that constitute the distinctive X2a clade, a clade that lacks close relatives in the entire Old World, including Siberia. The position of X2a in the phylogenetic tree suggests an early split from the other X2 clades, likely at the very beginning of their expansion and spread from the Near East.