Ascertainment bias in estimates of average heterozygosity.

Population geneticists work with a nonrandom sample of the human genome. Conventional practice ensures that unusually variable loci are most likely to be discovered and thus included in the sample of loci. Consequently, estimates of average heterozygosity are biased upward. In what follows we describe a model of this bias. When the mutation rate varies among loci, bias is increased. This effect is only moderate, however, so that a model of invariant mutation rates provides a reasonable approximation. Bias is pronounced when estimated heterozygosity is < approximately 35% Consequently, it probably affects estimates from classical polymorphisms as well as from restriction-site polymorphisms. Estimates from short-tandem-repeat polymorphisms have negligible bias, because of their high heterozygosity. Bias should vary not only among categories of polymorphism but also among populations. It should be largest in European populations, since these are the populations in which most polymorphisms were discovered. As this argument predicts, European estimates exceed those of Africa and Asia at systems with large bias. The magnitude of this European excess is consistent with the version of our model in which mutation rates vary across loci.     

An estimate of unique DNA sequence heterozygosity in the human genome

Summary Patients with recessive X-linked ichthyosis Patients with recessive X-linked ichthyosis (RXLI), one hereditary form of scaly skin, lack activity of the enzyme steroid sulfatase in all tissues studied. To investigate the molecular defect underlying the lack of enzyme activity, we prepared antisera against normal enzyme by injecting normal placental microsomal suspensions or partially purified steroid sulfatase into rabbits. Antibody activity was assessed by immunoprecipitation of detergent solubilized steroid sulfatase. In addition, we prepared rabbit antisera against RXLI placental microsomal suspensions. To detect immunologically cross-reactive material in patients' placentas, extracts were studied by immunoblot techniques and by competition with normal enzyme for antibody binding. Patients' extracts did not contain immunoreactive material co-migrating on electrophoresis with purified enzyme nor did they inhibit immunoprecipitation of normal enzyme. Sera from rabbits immunized with RXLI placental microsomes contain no antibodies to normal steroid sulfatase, as judged by their failure to immunoprecipitate normal enzyme or to react with normal steroid sulfatase on immunoblot. Thus the mutation in RXLI appears to reduce steroid sulfatase enzyme protein as well as enzyme activity. Portions of this material have appeared in abstract form in Clinical Research 31:564A, 1983 and 32:138A, 1984     

Allozymic variation as an estimate of heterozygosity in Belgian pig breeds

An electrophoretic survey of 13 enzymes corresponding to 19 loci has been carried out in Belgian Landrace and Pietrain pig breeds. Four of these enzymes have been shown to exhibit electrophoretically detectable polymorphism. The average heterozygosity per locus was found to be 0.066 in the Belgian Landrace and 0.028 in the Pietrain pigs.     

Sampling strategies for using female gametophytes to estimate heterozygosity in conifers

Summary Unbiased estimators of genotype and allele frequencies and their respective variances are obtained for loci identified by mendelian segregation in haploid female gametophytes from individual trees. By a minimum sampling variance criterion, the allocation of experimental effort between the number of female gametophytes analysed per tree and the number of trees sampled per population is examined for a fixed total amount of experimental effort. For estimating heterozygosity, the optimum sampling design for many (generally most) cases is three female gametophytes per tree, but may be more than three depending upon the true genotype frequencies in the population. For estimating allele frequencies, the optimum sampling design is one female gametophyte per tree except in cases where a strong negative correlation exists between alleles within genotpyes. Guidelines are discussed for determining a suitable number of female gametophytes to be analysed per tree in order to estimate heterozygosity.     

genhet: an easy-to-use R function to estimate individual heterozygosity

genhet is an R function which calculates the five most used estimates of individual heterozygosity. The advantage of this program is that it can be applied to any diploid genotype dataset, without any limitation in the number of individuals, loci or alleles. Its detailed manual should allow people who have never used R before to make the function work quite easily. The program is freely available at http://www.aureliecoulon.net/research/ac-computer-programs.html.     

A chromosome-specific estimate of transmission of heterozygosity by 2n gametes in potato

Polyploid plants are formed when numerically unreduced (2n) gametes participate in fertilization. Based on cytological and genetic analyses, modes of 2n gamete formation have been determined for a number of plant species. Gametes formed by a first-division restitution (FDR) mechanism contain nonsister chromatids near the centromere, whereas those formed by second-division restitution (SDR) contain sister chromatids. These mechanisms differ in the proportion of heterozygous loci they transmit intact to offspring. This paper estimates the transmission of heterozygosity on an individual chromosome basis through pachytene analysis of chromosomes of haploids (2n = 2x = 24) of Solanum tuberosum Andigena Group (2n = 4x = 48), a South American cultivated potato. Transmission of heterozygosity by FDR and SDR 2n gametes was calculated for 6 different cytogenetic assumptions. FDR was more than twice as effective as SDR in transmission of heterozygosity under all 6 scenarios. Rates of transmission of heterozygosity were similar in each situation. Transmission of heterozygosity by FDR was also compared with transmission of heterozygosity by tetrasomic inheritance and found to be approximately 50% more effective.     

An estimate of melanosome concentration in pigment tissues.

Concentration of melanosomes in various tissues has been unknown because of the impracticability of their direct quantification. Using an indirect approach comprising the estimation of melanin both in freeze-dried tissue samples and in isolated melanosomes, we obtained data on the amount of melanosomes in various pigment tissues. The concentrations of melanosomes found in the tissues were relatively high, not only reflecting the dark color of pigment tissues but also explaining their capacity to perform various functions ascribed to the presence of melanin.     

Estimation of average heterozygosity and genetic distance from a small number of individuals

The magnitudes of the systematic biases involved in sample heterozygosity and sample genetic distances are evaluated, and formulae for obtaining unbiased estimates of average heterozygosity and genetic distance are developed. It is also shown that the number of individuals to be used for estimating average heterozygosity can be very small if a large number of loci are studied and the average heterozygosity is low. The number of individuals to be used for estimating genetic distance can also be very small if the genetic distance is large and the average heterozygosity of the two species compared is low.     

Relationship between heterozygosity and genetic distance in the three major races of man

In pairwise comparisons of gene frequency data from the three major races of man, the single locus measures of the heterozygosity within and the genetic distance between races are shown to be strongly correlated across the loci coding for red cell proteins and enzymes. The intercept of the regression line of genetic distance on heterozygosity in protein enzyme loci is statistically insignificant. These findings suggest that the genetic variability at the enzyme and protein loci in man is probably maintained by a balance of mutation and random genetic drift. At the blood group loci, however, the observed relationship between genetic distance and heterozygosity does not follow the expectation of the neutral mutation hypothesis. These observations are discussed in terms of the changes in probability of identical monomorphism in two populations during the process of gene differentiation.     

Average heterozygosity revisited.

The estimate of heterozygosity and proportion of polymorphic loci for 33 red blood cell loci has been updated by the elimination of some loci of questionable status and the addition of data on 33 loci. The new figures for heterozygosity and proportion of polymorphic loci, .105 and .283, respectively, are based on 60 red blood cell loci of European origin populations. These values are less than those calculated by Lewontin in 1967, and furthermore they do not appear to be reaching an asymptote. At the present time, the red blood cell data and allozyme data for European populations have similar estimates of heterozygosity and proportion of polymorphic loci.     

Population structure of the forest Nentsi. V. F-statistics, genetic distances and the average heterozygosity (compared to the Nganasani)

Aspects of population structure within two of the least disintegrated "anthropological isolates" in north-western (forest Nentsi) and north-central (Nganasani) Siberia were analysed on the basis of 14 polymorphic loci. The mean FIS values were found to be 0.008 in the forest Nentsi and -0.038 in the Nganasani. The negative FIS in the latter may be due to avoidance of close inbreeding. This is not the case with the Forest Nentsi who prefer matings of the uncle-niece and first cousin's type. The mean RST(FST) values of 0.026 for the forest Nentsi and 0.009 for less heterogeneous Nganasani fall within the range of values found in subdivided human groups with a similar pattern of material culture and economy. Analysis of covariance and variance matrices containing gene frequencies for seven forest Nentsi and three Nganasani subdivisions indicate that the population structure of both groups is the product of the counterbalancing action of genetic drift and migration. Pairwise genetic and geographic distance matrices between subpopulations within both groups are highly correlated, allowing us to ascribe more than 90 percent of variation among subdivisions of the Nganasani and almost 70 percent in the forest Nentsi to the effects of geographic barriers, namely distance. Mean locus heterozygosity was found to be higher in the forest Nentsi (0.332) than in the Nganasani (0.286) reflecting pronounced difference in their histories.     

Natural heterozygosity in Candida albicans.

We subjected 16 Candida albicans clinical isolates to ultraviolet radiation and tested the survivors for auxotrophy. Six isolates displayed strongly biased auxotroph spectra: three yielded methionine auxotrophs, two yielded both isoleucine-valine and adenine auxotrophs, and one yielded lysine auxotrophs. We present evidence that auxotrophs arise by segregation from naturally occurring heterozygous states. The remaining isolates yielded few or no auxotrophs in an arbitrary sample (greater than 2,500) of survivors of irradiation. Our experiments indicate that C. albicans is diploid, although aneuploidy (2n + i) cannot be rigorously excluded. We discuss the possible utility of heterozygosity as a marker in epidemiological studies, and we discuss a rationale for the frequent occurrence of heterozygosity.     

Comfort of man in the city. An energy balance model of man — environment coupling

The powerful energy-balance systems approach was applied to the quantification of man-environment relations in an urban area. Nine special purpose energy-balance models of man-environment relations are summarized. Physiologic comfort is defined. Research resulted in the development of a general purpose man model for predicting the elements which can be used to derive the comfort of man in any environment as well as the magnitudes and directions of the various energy exchanges. The model has been applied to the special case of summertime thermal comfort of individuals in various parts of a large city (Sacramento, California) and has revealed quantitative information on the unique microclimates within a city.     

An estimate of large-scale sequencing accuracy

The accuracy of large-scale DNA sequencing is difficult to estimate without redundant effort. We have found that the mobile genetic element IS10, a component of the transposon Tn10, has contaminated a significant number of clones in the public databases, as a result of the use of the transposon in bacterial cloning strain construction. These contaminations need to be annotated as such. More positively, by defining the range of sequence variation in IS10, we have been able to determine that the rate of sequencing errors is very low, most likely surpassing the stated aim of one error or less in ten thousand bases.     

Mechanisms of loss of heterozygosity in retinoblastoma.

Retinoblastoma (RB) tumors arise when both alleles of the RB1 gene are inactivated by two mutational events (M1 and M2). M1 can be an initial germline or somatic mutation; M2 is frequently loss of heterozygosity (LOH), which makes the cell homozygous or hemizygous for the original mutation. LOH is the major mechanism by which many cancers are initiated. To further delineate the mechanism of LOH, we screened a total of 37 RB tumors for LOH by Southern blot analysis. The tumors were from 17 bilaterally and 17 unilaterally affected patients. Nineteen of 30 informative tumors (63%) from 27 patients showed LOH. Proximal and distal flanking markers on chromosome 13 were informative in 13 tumors, allowing evaluation of the mechanisms by which LOH occurred. Mitotic recombination was implicated in 6 (46%) of the 13 tumors.