J. G. Oakeshott

A twin study of ethanol metabolism

Blood alcohol measurements were obtained for 206 pairs of twins who had ingested a standard dose of alcohol (0.75 g/kg body weight) and repeat measurements were obtained for 40 of these pairs on a second occasion. The repeatability of the peak blood alcohol concentration (BAC) was 0.66, that of the rate of elimination was 0.39, and that of the time to peak BAC was 0.27. Only a small portion of the nonrepeatable variance could be explained by measurement error or drinking experience. It is concluded that short-term environmental factors exercise considerable influence on alcohol metabolism, particularly in the absorption phase. All of the repeatable variance in peak BAC and rate of elimination was due to genetic factors. Only a small proportion of any of the genetic variance could be explained by individual differences in weight, adiposity, or lung function. Likewise, these three factors were unable to account for the fact that females had higher BACs than males during both absorption and elimination.

A Twin Study of Psychomotor and Physiological Responses to an Acute Dose of Alcohol

A battery of psychomotor tasks and physiological measures was administered to 206 pairs of twins before alcohol and then three times at hourly intervals after they ingested a standard dose of ethanol (0.75 g/kg body weight). Repeat measurements were obtained for 41 of these pairs on a second occasion. Performance on motor coordination, standing steadiness, pursuit rotor, arithmetic computation, and reaction-time tasks deteriorated after alcohol, but decrements on the five tasks were generally independent of each other. Measurements of blood pressure, pulse rate, and skin temperature were all elevated following alcohol intake, but these responses were also uncorrelated. The variance in many of these measures increased after alcohol. An analysis of covariance structure revealed that most of this additional variance exposed by alcohol was genetic in origin, particularly for standing steadiness, pursuit rotor, arithmetic computation, and pulse rate. Up to 50% of the variance in body sway after alcohol was estimated to be due to genetic factors expressed only under the influence of alcohol. Although significant correlations were found with blood alcohol concentration, previous drinking experience, and the personality trait Extraversion, little of the genetic variance exposed by alcohol could be explained by these predictors. It is concluded that the sources of the considerable genetic variation affecting performance under alcohol must be sought elsewhere.

Population genetics of the metabolically related Adh, Gpdh and Tpi polymorphisms in Drosophila melanogaster I. Geographic variation in Gpdh and Tpi allele frequencies in different continents

Among Australasian populations from above 32.5° latitude there is a significant negative relationship between GpdhF frequency and distance from the equator which is not explained by gametic disequilibrium with the linked inversion In(2L)t. This is consistent with the associations reported earlier for GpdhF among populations covering comparable latitudes in North America and Europe/Asia. By contrast, Tpi allele frequencies are found to be significantly associated with distance from the equator in Australasia but not North America or Europe/Asia. The Tpi pattern in the different zones is essentially the same as that reported earlier for the Acph polymorphism, which maps only 0.2 cM away from the Tpi locus.There are now ten enzyme polymorphisms in D. melanogaster which have been screened for latitudinal associations in Australasia, North America and Europe/Asia. Allele frequencies at six of these loci show significant relationships with distance from the equator which are consistent across all three zones. These latitudinal associations are more prevalent for Group II than Group I enzymes. Values of genic heterozygosity averaged over the ten polymorphic loci and eleven other monomorphic systems do not vary with latitude but differ substantially between zones. Values of Neis genetic distance between North American and European/Asian populations calculated from all 21 systems are equivalent to subspecific differences elsewhere in the genus.

Observations on the extent and temporal stability of latitudinal clines for alcohol dehydrogenase allozymes and four chromosome inversions in Drosophila melanogaster

Previously we have presented evidence of large-scale latitudinal clines in the frequencies of four chromosome inversions and alleles at six enzyme loci in populations of D. melanogaster in Australasia, Asia and North America. Subsequent sampling by others in Japan and western U.S.A. has failed to repeat this observation for the steepest of the clines (alcohol dehydrogenase and the four chromosome inversions). We argue that this failure reflects the few populations and small latitudinal range sampled in these later studies. From extensive sampling over a long latitudinal transect in Australasia we here document Adh and inversion clines which are virtually identical to those originally obtained in different Australian populations four years earlier. We also repeat our observation that the Adh cline is largely independent of the cline in the linked inversion In(2L)t. We therefore retain our original conclusion that these polymorphisms are subject to natural selection. However the new Australasian data do not indicate an association between Adh and maximum rainfall which had been evident in the earlier data for Australasia, Asia and North America. We therefore retract our claim that the selective agent on Adh is related to rainfall.

Lung function in an Australian population: contributions of polygenic factors and the Pi locus to individual differences in lung function in a sample of twins

A study of lung function in 203 twin pairs aged 18-34 years living in Sydney detected significant genetic variation in females and males. There was no evidence of family environmental effects in either sex and most of the repeatable variation in females was heritable. However, there was evidence for systematic environmental differences between males affecting lung function so that the heritability was lower in males (about 0.6) than females (about 0.8). An effect of smoking on lung function was detected but accounted for less than 3% of the variance. Lung function in females was greater in the M subtype heterozygotes at the Pi locus than in the M subtype homozygotes or in other Pi phenotypes with low alpha 1-antitrypsin activity. The Pi polymorphism accounted for approximately 9% of the total variance in female lung function. No effect of the Pi locus was found in males.

An attempt to measure selection coefficients affecting the alcohol dehydrogenase polymorphism in Drosophila melanogaster populations maintained on ethanol media

Eleven populations polymorphic for Adh F and S alleles were established from wild-caught D. melanogaster. Seven of the populations were founded from mass collections each of several hundred flies and the other four were isofemale lines. Subcultures from all eleven were maintained on one of four different types of medium—standard laboratory medium, standard media supplemented to 3% or 9% (v/v) ethanol, and simulated wine seepages. These subcultures were rescored for F and S gene frequencies after 10, 20 and 30 generations. Maximum-likelihood methods were then used to estimate selection coefficients among the Adh genotypes and analyses of deviance were carried out to test the coefficients against hypotheses of neutrality and various modes of selection. No significant selective changes in Adh frequencies were observed in the seven mass cultures on any of the four different media types. However, highly significant selective effects were detected in the four isofemale lines; these effects were homogeneous across the four lines and the four media types and the underlying fitness set was estimated as 1.00:1.04:1.09 for S/S:F/S:F/F.

Effects of the protease inhibitor (Pi) polymorphism on alpha-1-antitrypsin concentration and elastase inhibitory capacity in human serum

The concentration of alpha-1-antitrypsin (AAT) and its elastase inhibitory capacity (EIC) have been investigated in vitro in sera from 1688 healthy Canberra blood donors typed for electrophoretic variants of the protease inhibitor (Pi) locus. Nine Pi alleles were recorded in the sample, of which M1 was found at a frequency of nearly 70% and the other eight were each at frequencies below 15%. As a class, heterozygotes among the three Pi M subtype alleles, M1, M2 and M3, have higher means and lower variances for AAT and EiC than do the three M subtype homozygotes. Among the three homozygotes M1M1 has highest AAT and EIC and among the heterozygotes dominance in M1M2 and M1M3 is towards or beyond the high M1M1 values. Of the six other Pi alleles recorded, two (F and G) have similar values to the M subtypes but the other four (I, N, S and Z) have lower values. The patterns of means and variances in AAT and EIC for the different M subtype genotypes do not support the precise threshold function postulated by Martin and Oakeshott (1983) to relate activity to Darwinian fitness. Nevertheless, several aspects of the results are consistent with a general positive relationship between activity and fitness.

Association between alpha-1-antitrypsin types and the common cold

Associations have been found between self-reported cold symptoms and Pi type in 84 pairs of identical twins. The risk of cold symptoms relative to MM phenotypes was 1.2 times greater in MS and 2.5 times greater in MZ individuals. Up to 9% of variance in cold symptoms could be attributed to Pi type, representing at least 20% of the total genetical variance.