Heredity 55 (1985) 341—353 The Genetical Society of Great Britain Received 20 March 1985 Lerner's concept of developmental homeostasis and the problem of heterozygosity level in natural populations
G. Livshits and E. Kobyliansky Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.
In recent years adherents of the neutral mutation hypothesis have conducted a variety of statistical tests concerning the applicability of their theory to data of biochemical genetic polymorphism in natural populations. From the other side, the involvement of natural selection as a main evolutionary force responsible for the observed levels of polymorphism and heterozygosity have also been proposed in numerous field studies and theoretical considerations. However, none of these hypotheses completely and satisfactorily explains the collected data. We believe that one of the main causes of the discrepancy in theories is that the variability at each locus is considered independently in both of the above- mentioned approaches. Yet, it was suggested long ago, and now there is an increasing amount of evidence indicating cooperation between different loci which can influence the variability at each of them. Thus we think that the use of models considering the genome as a suit of independent genes is a priori expected to decrease the efficacy of the approximation. In the present review we attempt to draw attention to findings of interdependence of the variability of different characters and its possible limiting action on the growth of genetic diversity in natural populations. We do not try to give a universal explanation for the processes acting in populations and determining levels of heterozygosity. However, to our mind, the solution of the discussed question requires consideration of genes in their interactions.
INTRODUCTION of 4 of each other". Existing electrophoretic evi- dence indicates that the heterozygosity of Theexplanation of genetic polymorphism in numerous investigated species are below the lowest natural populations is a controversial issue among theoretically expected level as derived from neutral proponents of the neutral theory of protein evol- theory models (Nei and Graur, 1984; Nevo, ution as opposed to those who favour the selection 1983a). Fig. 1, extracted from Soule's (1976) and hypothesis (for review, see Nei, 1984; Nevo et aL, Nei and Graur's (1984) reviews show that even for 1984). The neutral mutation hypothesis argues that u values of i07 and i0, the observed heterozy- the degree of heterozygosity (H) at steady state is gosity pattern for equilibrium populations of proportional to the effective population size (N) various animal species, markedly deviates from the and mutation rate per locus (u): H = neutralist model. Although in numerous and 1—[1/(4Nu+1)](Kimura and Crow, 1964). Yet diverse animal species the heterozygosity level and the range of average heterozygosity per locus per the effective population size are highly correlated individual among species which are numerically and this accounts for about half (r =0.49,Soule, extremely different is surprisingly narrow, being 1976 or r2 =043,Nei and Graur, 1984) of the 005—0- 18 for the overwhelming majority of species variation of H, the slope of the observed regression and only exceptionally 000-026 (Nevo, 1978; line is strongly and significantly lower than expec-
Nevo et aL, 1984). To cite Lewontin (1974, p. 208): ted (fig. 1). — "Since there is no reason to suppose that mutation Themean observed heterozygosites (H) are rate has been specially adjusted in evolution to be very similar for extremely different human popula- reciprocal of population size for higher organisms, tions (Nei and Roychoudhury, 1974; Altukhov et we are required to believe that higher organisms aL, 1981a). Using the above-mentioned formula including man, mouse, Drosophila and the horse- one can calculate the expected H in some human shoe crab all have population sizes within a factor populations. Neel (1980) estimated that in 342 G. LIVSHITS AND E. KOBYLIANSKY
interactionsbetween them. In the present paper, we will attempt to demonstrate the existence of such interdependence between different loci (characters) and its limiting influence on the popu- lation heterozygosity level. We will consider associations between loci (and characters) whose chromosome linkage is unknown.
DATAAND DISCUSSION
L9N 1. Relationship between different sets of Figure 1Expected (curves) and observed (points and shaded characters and heterozygote superiority field) heterozygosites (H) in various animal populations differing in population size (N). The shaded field is from Table1 provides data on the relationship between Soule's (1976) data; the points are from Nei and Graur's (1984) data. The first curve corresponds to the stepwise heterozygosities at various biochemical loci and mutation model, assuming that the mutation rate is the variability of morphological and several other lO locus/generation. The second curve represents the (non-biochemical) characters among such dispar- same model with a mutation rate of 1Olocus/generation. ate life forms as plants, invertebrates and verte- brates, including humans. Although for some species a relationship was not found (we know of American Indian populations, mutations resulting two such examples—see Hanford, 1980; in electrophoretic variants of a series of 28 blood McAndrew eta!.,1982),for the majority of species proteins occur at a rate of 1.6x105/locus/ and variables it was consistently demonstrated that generation). Using a different approach for a Mos- an increase in the heterozygosity level leads to a covite population, Altukhov (1980) obtained a decrease in the morphological variability. This is similar value for the average mutation rate (6 x true, for instance, for such regular quantitative l0/locus/generation). If we accept Nei and traits as height and weight, as well as for various Graur's (1984) approach, that effective population estimates of fluctuating asymmetry (the level of size is not the size for a local population but for the relationship in such cases can reach r = the entire species, then the heterozygosity level in —0.961).One can see additionally that compared Homo sapiens should be very near to 1, i.e., much with homozygotes, heterozygous individuals were higher than the H values obtained for any of the characterised by a higher rate of growth and sur- three major human races (0.099-0.168) for vival and a more economical rate of oxygen con- different sets of enzymatic loci (Nei and Roy- sumption (table 1). These findings were applicable choudhury, 1974; Ryman et a!., 1983). Thus the both at the individual and the population levels. degree of heterozygosity and polymorphism in a In our study (Livshits and Kobyliansky, 1984) natural population is significantly lower than that based on 250 young men sampled from a single predicted by the neutral theory. Since heterozygous population, we investigated the dependence of the individuals are usually deemed more fit than variability of 48 anthropometric features on the homozygous ones, the heterozygosity level in the degree of heterozygosity at four blood group loci. population should be higher than expected from Of the traits studied, 19 showed a certain relation- the neutralistic model, It follows, then, that the ship, while six were independent. We found that observed heterozygosity is even less satisfactorily the frequency of modal individuals (average± explained by a concept of heterozygote superiority. 0'67 S.D.) was highest in the group heterozygous The discrepancy between the predicted and the at four loci, diminishing proportionately with observed heterozygosity in natural populations is decreasing heterozygosity levels (table 2). The usually explained on the basis of the "recent bottle- degree of heterozygosity was also significantly neck" hypothesis (Nei eta!., 1975; Nei, 1984). This inversely correlated with the coefficient of variation explanation seems to us very tenuous, and at least of the morphological characters albeit positively for several species it is entirely groundless (Soulé, associated with the kurtosis values. 1976). Multivariate analysis confirmed the results and At the same time, in the cited studies, the varia- showed that in multidimensional space heterozy- bility of each locus was considered to be indepen- gotes tend to group near the center of a combined dent of other loci, thus not accounting for possible distribution of several independent traits (Koby- HETEROZYGOSITY IN NATURAL POPULATIONS 343
Table IRelationship between different sets of traits
Biochemical loci heterozygotes Morphological or other characters Relationship Species Source
*4Est loci of Embryonal survival Pos. Pinus sylvestris (L) Pravdin et a!., 1982 endosperm relationship (Flora) 5*21 enzyme Mean annual basal area increment r =080-090 Pinus rigida (Flora) Ledig et. at 1983 locil **pGMI and 2, Fluctuating asymmetry =right-left r —0947 Elliptio complanata, Kat, 1982 GPI, LAP, HEX, MDH difference in number of plicae r= —0961 Lampsilis radiata on labial palps (Mollusca) *LAP, GOT, GPI, PGM,Weight (mean) growth r =090 Crassostrea virginica Singh and EST, XDH, AO Weight CV r=—O8l (Mollusca) Zouros, 1981 *GPI PGM, LAP, EST Oxygen consumption rate r=—081 Crassostrea virginica Koehn and (Mollusca) Shumway, 1982 GPI, PGM, LAP, Individual energy budgets —025 Mulinia lateralis Garton el at, 1984 EST, STDH, PEP p
Table 2Relationship between the heterozygosity and morphological variability of four blood group loci in a human population
Statistical Parameter treatment of of Degree of heterozygosity association distribution 0 1 2 3 4 r p
Height of body M 0368 0365 0597 0538 0727 091 003 CV 35•6 398 335 313 283 —083 008 Kurtosis —181 —l47 —047 050 186 098 001 N 19 52 77 39 11 Bi-trochanertic diameter M 0278 0•490 0500 0486 0600 086 006 CV 425 367 37•0 387 333 —078 012 Kurtosis —173 —101 —095 —087 008 092 003 N 18 51 78 37 10 Mesosternal chest circumference M 0421 0483 0500 0564 0727 094 002 CV 401 389 375 346 283 —093 002 Kurtosis —031 —079 —080 —060 186 064 026 N 19 54 78 39 11 Interocular diameter M 0368 0547 0410 0579 0727 094 002 CV 427 35•1 358 308 283 —089 004 Kurtosis —14l —073 —123 —050 186 081 009 N 19 53 78 38 11 Chelion-chelion length M 0474 0519 0'436 0474 0727 063 026 CV 389 366 368 346 270 —093 0•02 Kurtosis 0038 —0844 —1216 —103 076 024 025 N 19 54 78 38 11 Palmar length M 0333 0500 0500 0•590 0800 095 001 CV 39•4 353 366 315 236 —092 003 Kurtosis —152 —098 —096 —046 450 080 009 N 18 54 78 39 10 M—Frequency of modal individuals (average SI).) CV—Coefficient of variation N—Sample size
interdependence? When such correlation is against environmental insults, whereas deleterious revealed in comparisons of several conspecific genes may reduce the buffering below a threshold populations having a common origin and differing level. This view is supported by analysis of in the levels of inbreeding, it is evidently attribu- individuals with congenital anomalies, like cleft table to the convergent influence of inbreeding on palate and cleft lip, which have shown that there the various loci (Kobyliansky and Livshits, 1983). is an increase in fingerprint asymmetry not only However, when heterozygous and homozygous in affected individuals but also in their relatives individuals (for a few loci) from a single panmictic (Woolf and Gianas, 1976; 1977). In agreement population are compared, inbreeding is insufficient with these findings are the observations that per- to explain the relationship. Better then to turn to sons with different genetic disorders (such as Lerner's (1954) concept of developmental homeo- Down's syndrome and cleft palate) have sig- stasis and his suggestion that phenotypic variabil- nificantly increased dental asymmetry (Sofaer, ity is inversely correlated with the level of heterozy- 1979; Barden, 1980). Recently Malina and Bus- gosity. Shapiro (1970) suggested that develop- chang (1984) found that mentally retarded mental paths represent the outcome of coadapted individuals show significantly greater genetic systems which have evolved because they anthropometric asymmetry than normal produce phenotypes selected over time. Polygenic individuals. That the fluctuating asymmetry is systems may buffer the developmental process apparently a good indicator of overall develop- HETEROZYGOSITY IN NATURAL POPULATIONS 345
Table 3Dermatoglyphic pattern differences between mor- provided a similar analytical solution. This author phologicallymultimodaland multiextremal individuals. has shown also that the correlation between For comparison purposes we chose from our sample only individuals who were modal or extremal for five, or sampled average heterozygosity and genomic at least four, independent traits. The studied traits are given average heterozygosity in a random individual in table 2 decreases as the average heterozygosity in the population increases, although the absolute value Multimodal Multiextreme of the correlation is largely dictated by the propor- Dermatoglyphic pattern md. (N =74) md. (N =63) tion of loci sampled from the genome. Thus the Asymmetry 780±050 < 9•43±0•55 suggestions that the measured heterozygosity may merely reflect generalised genomic heterozygosity, (Ri-Li)2 and that the sampled highly homozygous Asymmetry 2600±642 < 4351±859 genotypes represent more inbred individuals, are =(AL—LR)2 tenuous. Asymmetry 5883 1695 <14690±4554 Soulé (1982) proposed a hypothesis that could =(SL—SR)2/100 Asymmetry 1175±2478 >1060±2429 explain some aspects of Lerner's developmental =(QL—QR)2 homeostasis in terms of the random events that TRC-diversity 684±045 < 706±043 occur during growth and development. On the basis of Lande's (1977) analysis, which compared = KQT2/5)/5 homologous structures differing in the number of Shanon diversity 061±003 < 066±003 similar components and proved that variation of CV of URC on Dl 161 < 21.7* the character is negatively dependent on the num- CV of URC on D4 26•3 < 34.8* CV of RRC on Dl 341 < 39.5* ber of components involved, Soulé (1982, p. 762) CV of RRC on D4 323 < 46.5* argued that "homozygotes should occur with greater frequency in the tails of phenotypic distri- Here Ri-Li is the difference in ridge Counts (RC) between the butions, while heterozygotes should occur near the homologous fingers on the right (Ri) and left (Li) hands. XL mean with increasing frequency". The corollary of and R =maximalfinger ridge count (max FRC) —mmFRC on the left and right hands, respectively. SL and SR are q — this theory is that variability increases and Q2/5where qi is FRC and Q is total RC for left or right hands, buffering of homozygote ontogenesis decreases as respectively. Ki is the sum of the RC of the ith pair of a reaction to the accidental perturbations and homologous fingers and QT is the total RC on both hands. insults that occur in the course of development. The Shanon diversity is the information =— Pi In Pi, where If we accept that a breakdown in develop- Pi is the frequency of loops (or whorls or arches) on the 10 fingers of each individual. URC and RRC are ulnar and radial mental homeostasis is a pathological expression ridge counts, respectively, on digit 1 (Dl) and digit 4 (D4) of genetic characters, then we can expect an * Statisticallysignificant difference (p <0.05) increased frequency of pathology in homozygotes and extreme phenotypic variants. Indeed, Ford mental stability is supported also by findings on and Bull (cited by Soulé and Cuzin-Roudy, 1982) non-human organisms (e.g., Leary etaL, 1984, have had already in 1926 examined 7000 herring noted that in fish deformed individuals were more skeletons for vertebral fusions and found the asymmetricatfiveindependentbilateral incidence of these abnormalities to be much greater characters). in fish with either low or high number of vertebrae. Ledig et al. (1983) suggested that the estab- Comparison of data on congenital malformations lished negative correlation between heterozygosity in Japanese infants with the available information at some loci and variability at others may be on Caucasian and Negro populations, has shown explained by the fact that the measured heterozy- that the biological impact of congenital malforma- gosity is simply a reflection of the general heterozy- tions is very similar for all populations (Ned, gosity of the genome. Therefore, individuals 1958). Since more such children exhibit multiple homozygous for the sampled loci suffer from major defects that would be expected on the basis inbreeding depression. Mitton and Pierce (1980) of the individual frequencies of these defects, Neel simulated a correlation between the level of concluded that a significant part of human con- genomic heterozygosity of 100 polymorphic loci genital defects are segregants (phenodeviants) and that estimated from subsets of sampled loci. resulting from the existence and functioning of Their estimations seem to be rather insensitive to complex genetic homeostatic systems. A U-shaped the heterozygosity of the whole data set and to the mortality curve associated with birth weight and distribution of heterozygosity across loci. An alge- showing correlation of mortality with prematurity braic approach to this issue by Chakraborty (1981) of infants was described by Terrenato et al. 346 G. LIVSHITS AND E. KOBYLIANSKY
(1981a, b) and Ulizzi eta!.(1981). A similar findings on heterozygote advantages (partly pres- observation was made by Altukhov and co-workers ented in the first section of this review) all (Altukhov, 1980; Botviniev eta!.,1980; Altukhov unequivocally suggest that selection is highly eta!.,1981b). These investigators reported that involved in genetic differentiation of populations morphologically average newborns and infants (by and that random factors are unlikely to be prime stature and weight) are characterised by a sig- movers of genetic differentiation in most species nificantly low frequency of diverse diseases (e.g. studied in the cited review (Nevo eta!., 1984). pneumonia,congenital malformations). An addi- Nevertheless, as has already been noted, heterozy- tional finding of these investigators was that sick gosity and also the level of polymorphism for children (e.g.,withpneumonia) display lower enzymatic loci are clearly below the lowest levels levels of average biochemical heterozygosity (loci predicted by the random events model or by the PGM, ACPH, MNSs, Rh) per locus, and a higher heterotic model (fig. 1). frequency of rare antigen combinations as well as Presumably this is attributable to the fact that rare electrophoretic protein variants than do the heterozygosity is fairly well delimited and any healthy children. The considered correlations increase in it is accompanied by the aforemen- clearly point to stabilising selection as the most tioned heterotic effects. However, when these suitable factor for controlling the levelof develop- limits are exceeded there is a breakdown of mental homeostasis. Confirmation of this has been developmental homeostasis and a general decrease obtained both from empirical observations as well in fitness. This hypothesis is illustrated in fig. 2 as from theoretical consideratios of the problem. adapted from Vrijenhoek and Lerman (1982). The As an example, we note that in different human horizontal axis represents individual heterozygos- communities the progress made in health care has ity, reaching an optimum "Op" in a panmicitic led to reduction of both the stabilising effect and population. On the vertical axis, representing the the intensity of selection (Terrenato eta!., 1981b; degree of developmental homeostatis, the corre- Terrenato, 1983). Wright (1969) introduced an sponding point in M (maximal level). From point optimum selection model in order to examine situ- Op, on the abscissa, heterozygosity can increase ations in which an intermediate phenotypic value by means of interpopulation and interspecies shows maximum fitness. According to this model hybridisation. The latter may lead to a general the fitness decreases as the squared deviation of incompatibility between gene complexes coadap- the phenotype from the optimum phenotype. ted within each population or species, resulting in Recent mathematical analyses of the relationship a breakdown of developmental homeostasis. The between fitness and the multiple-locus genetic state numerous examples of sterility and multiple con- of an individual have also shown that individual genital anomalies of hybrids are well documented fitness should increase with heterozygosity. It was (Grant, 1963). A strong disturbance of develop- found both analytically (Smouse and Ledig, 1984) ment can be related not only to chromosomal and by simulation methods (Turelli and Ginzburg, imbalance, but also to differences in one or several 1983) that when using a set of two and/or multiple- loci as was established in old classical studies on allele loci both in the multiplicative overdomin- maize (Beadle, 1930; 1933) and Drosophila ance model as well as in the additive overdomin- ance model, the average fitness monotonically decreases with the number of homozygous loci, M but increases with heterozygosity at stable multi- . cn locus polymorphisms.
2. Limitsof heterozygote superiority Nevo(1983a, b; 1984) collected a vast amount of data on biochemical polymorphism and heterozy- O.c gosity (H) in over 1100 plant and animal species op and their dependence on various ecological, demo- Heterozyqosity level graphic and life history parameters. The parallel inbreedinq Hybridisation genetic patterns observed for many different Figure 2 Scheme of the relationship between the degree of species and the significant correlations between developmental homeostasis and the individual level of heterozygosity and polymorphism with some vari- heterozygosity. X reflects the different species hybridi- ables and their combinations, together with the sation. HETEROZYGOSITY IN NATURAL POPULATIONS 347
(Gowen, 1931). A disparity between nuclear and cent. Vogel (1984) pointed out that, even excluding cytoplasmic genes can also be considered a cause multiple heterozygotes for 114 recessive diseases of the hybridisation disadvantage (Markert and (occurring practically in each population and with Ursprung, 1971). If speciation occurs by a gradual each disease having a homozygote frequency of accumulation of differences (irrespective of 10-v), approximately 31 per cent of the population whether by point mutations or by duplications) of the state was heterozygous for one of the 114 then we should expect deviation from the norm metabolic diseases mentioned. In reality (and already in populations intermixing within a based on McKusik, 1983), Vogel supposed that in species. It is reasonable to assume that this devi- each population each individual might be ation will be related to the measure of differenta- heterozygous for one or several recessive genes ition and level of isolation prior to intermixing. withdeleterious effects in homozygotes. For instance, in children from intermarriages in Obviously, these genes form an enormous genetic human populations temporally and geographically load, held in the population by a balance between isolated, a slower rate of development of some selection and recurrent mutation. In each gener- morphological traits was observed (Nikityuk and ation the divergence from the expected rate of Filippov, 1975) as well as an increase in the mutation at a given locus will be reduced by the frequency of several congenital anomalies (Altuk- affection probability (Morton, 1982): hov, 1980). A decrease in the heterozygosity level in a popu- S=e—{[x+> q2s+2 q(1—q). s/i] lation from point Op (on axis X) represents inbreeding. The negative influence of inbreeding +[ qs—q2s—2 q(1—q)shJF}, depression on animal and human development is well known. However, there are several additional where the outer brackets contain the so-called pan- facts supporting the idea that the individual and mictic load, and the inner brackets—the inbred intrapopulational levels of heterozygosity and load, x is the probabilty of a particular environ- polymorphism are well delimited. These levels mental cause of affection, s and sh are the seem to be a result of opposing forces operating coefficients of selection against homozygotes and on the individual and the population, nanely, (1) heterozygotes, respectively, and F is the coefficient the advantage of heterozygotes under normal con- of inbreeding. ditions and the possible neutrality of some alleles; It is evident that as the functional importance and (2) the disadvantage of heterozygotes in of the locus-trait increases, the affection probabil- extreme environments, segregation load and the ity also increases, so that at some loci monomorph- possible disharmonisation of genotype and ism can be expected and therefore, a priori, the phenotype by a high level of combination originat- heterozygosity and polymorphism levels must be ing from high intra- and inter-locus diversity. The lower than predicted from the neutral model. advantage of heterozygotes has already been con- Based on this reasoning and on observational data, sidered here. As for the disadvantage this deserves Altukhov (1974, 1982) postulated the duality of discussion at some length. To begin with, any the structural-functional organisation of the expected genetic diversity is decreased by the eucaryotic genome. This concept regards the poly- destructive action of the majority of new muta- moprhism of proteins as a relatively neutral varia- tions, which must be eliminated from populations. bility related to the secondary adaptive properties Altukhov et aL (1983) estimated the spontaneous of species, and sees the genetically monomorphic mutation rate in the pine tree to the 19 X proteins as markers of functions so basic that varia- io- locus/generationin early embryonal stages bility normally is biologically intolerable. The and showed that negative selection pressure at the differences between species, for polymorphic loci, seedling stage can reach 100 per cent. Various are in principle similar to those between popula- epidemiological studies of human populations tions within species, i.e., they are differentiated by have given extremely high estimates of the number the frequency of the same allele or by particular of genetic diseases. According to Matsunaga's alleles, specific only for them. At monomorphic (1982) review, about 5 per cent of all live-born loci the differences between species are qualitative, children in Northern Ireland suffer from a serious i.e., the species are discrete and are made unique non-chromosomal genetic disease. Similarly, data by these characters as are different genotypes available to him from British Columbia indicated within species. Carson (1975) formulated a con- that the frequency of afflicted children among cept closely resembling the described hypotheses. 756,304 live births over 21 births reached 405 per He considered two systems of genetic variability— 348 G. LIVSHITS AND E. KOBYLIANSKY
"open" and "closed"—the first representing poly- occur more slowly with an increasing level of poly- morphic loci, which slightly influence individual morphism. As is well known, inversions and some fitness, while the second is stable, with only inter- other chromosomal aberrations may be mechan- specific differences. isms preventing segregation and, thereby, decreas- The expectation that polymorphism should be ing genetic diversity in panmictic populations restricted to only part of the genome is in agree- (Dobzhansky, 1970). ment with the principle of "polymorphism generat- Lewontin et al. (1978) considered the condi- ing more polymorphism" which advocates that tions necessary for a stable equilibrium at multial- new mutations are more likely to occur at heterozy- lelic loci and showed statistically that heterosis gous that at homozygous loci (Ohno, 1970). alone is not a mechanism for maintaining many Indeed, a high correlation (r=0.7-0.9)was alleles at a locus. Rather they found that even when observed in some organisms between the frequency all heterozygotes are more fit than homozygotes, of new mutations and rare alleles on the one hand, the proportion of fitness arrays that will lead to a and the "old" polymorphism level at a particular stable equilibrium of six or seven alleles is vanish- locus on the other (Koehn and Eanes, 1976; Altuk- ingly small. If this finding is at least approximately hov eta!., 1983). applicable to multilocus models, then we should Moreover, the existing heterozygosity is per- expect an even fewer number of alleles per locus haps also controlled by selection since, as stated than is predicted by the monolocus model. Indeed, by Vogel (1984, p. 410), "heterozygotes have, as a Turelli and Ginzburg (1983), in their computrer rule, about 50 per cent of the normal enzyme simulation analysis of multilocus models, found activity", which "being sufficient under normal that even for three unlinked diallelic loci with a living conditions, might very often lead to a relative polymorphism threshold of only about 05 deficiency of a normal metabolite or to an unusual per cent of the random initial conditions and increase of an abnormal one, if the metabolic path- matrices produced stable three-locus poly- way is burdened by special external or internal morphism. conditins and influences". The conclusion of this study, as well as of Lewontin et al.'s (1978) theoretical paper, are in agreement with results obtained in field investiga- 3.Interlocus interaction and genetic diversity tions of numerous and diverse organisms. In 20 level in populations randomly selected species of plants, invertebrates Thenormal action and functioning of each organ, and vertebrates, shown in table 4, about 92 per of physiological processes and the performance of cent of the electrophoretically studied loci have anorganism as a whole, depend on harmonic been found to be mono- or diallelic. cooperation between loci. In physico-chemical There are other observation evidences support- terms this means a conformity in the structure of ing our hypothesis of selection limiting genetic the interacting gene products as well as in the variability and heterozygote level in populations: concentration of these products. The majority of (a) Molecular evidence The analysis of molecular biochemical reactions in an organism, including structure and genetic variation of enzymes showed all enzyme-catalysed processes, proceed through a significant correlation between enzyme poly- more than one step, so that the reaction kinetics morphism and sub-unit molecular weight in such do not depend only on initial reactants and final varied species as Drosophila and Homo sapiens products. The final step depends on the slowest (Brown and Langley, 1979; Koehn and Eanes, stage which can occur in any sequence of the 1979). general chain of reactions (the "rate controlling Since mutations are errors introduced into the step"). Thus the optimal interaction is dictated DNA or occurring at any stage of the cellular by the qualitative and quantitative conformity protein biosynthesis, one would assume that between various non-allelic gene products. individual and populational heterozygosity is The number of all possible combinations simply a function of the genome or of the protein (without transpositions) formed from n alleles at values. However, this is not the case. Results of m loci is N={(n+1)mnm]/2m, which means that analysis of the variance of heterozygosity by gene there is a progressive increase in N, proportional and species showed significant effects due to both to the number of alleles in the mth degree. Such (Brown and Langley, 1979). Moreover, these inves- genetic diversity, augmented by Mendelian segre- tigators have also found that the heterozygosity of gation of non-linked loci, should mean that the a certain gene may be more dependent on other creation of the internally co-adapted genome will gene effects than on its derivative protein. Com HETEROZYGOSITY IN NATURAL POPULATIONS 349
Table 4 Frequency distribution of polymorphic gene level per population in different species (only electrophoretic analysis results are presented) Number Number of of Number of alleles perlocus studied studied Species and No. 1 2 3 4 5 6 7+ loci populations Reference
1 0705016500960024 0-0040006 0 28 28 Barley (Flora) Nevo et a!., 1979 2 0861 0-092 0047 0 0 0 0 13 8 Dismodium (Flora) Schaal and Smith, 1980 3 0-650 0-175 01250025 00250 0 20 2 Xerocrasse seelzenii (Mollusca) Nevo et a!., 1981 4 0525 0-275 0125 0025 0-050 0 0 20 2 X. erke!ii (Mollusca) Nevo et a!., 1981 5 0-758 0232 0-010 0 0 0 0 22 9 Armadillidium vulgare (Crustacea) Beck and Price, 1981 6 0-566 03300087 00170 0 0 23 5 Gledia captiva (Insecta) Moran el a!., 1980 7 03200560 0-040 0-0800 0 0 25 1 Drosophila melanogaster (Insecta) Band, 1975 8 0-909 0045 0045 0 0 0 0 22 1 Sarotherodon andersoni (Pisces) McAndrew and McJumdar, 1983 9 0-818 0-136 0045 0 0 0 0 22 1 Sarotherodonjipe (Pisces) McAndrew and McJumdar, 1983 10 0-536 0-407 0056 0 0 0 0 25 20 Coregonus albula (Pisces) Vuorinen et at, 1981 11 0-695 0-233 0-069 0-003 0 0 0 28 11 Frog (Amphibia) Nevo and Yang, 1982 12 0-812 0158 0-029 0 0 0 0 22 20 Lizard (3 species) (Reptilia) Gorman et at, 1975 13 0-543 0-276 0-108 0-056 0-017 0 0 23 9 Peromyseus (Mammalia) Loundenslager, 1978 14 0-555 0-111 0-333 0 0 0 0 18 1 Microtus (Mammalia) Nygren and Rasmuson, 1980 15 0-907 0-093 0 0 0 0 0 23 18 Moose (Mammalia) Ryman et a!., 1980 16 0-729 0-179 0-079 0-013 0 0 0 14 10 Rat (Mammalia) Beck et a!., 1981 17 0-876 0-099 0-025 0 0 0 0 27 3 Gerbil (Mammalia) Nevo, 1982 18 0-545 0-364 0-091 0 0 0 0 22 1 Homo sapiens (Mammalia) Altukhov et at, 1981a X 0-717 0-209 0-060 0-011 0-003 0-001 0 23 150 Average per population parisons of intralocus heterozygosity carried out that form interlocus hybrids. They found that the on proteins with different quaternary structure in third group exhibits a very low percentage of poly- numerous species ranging from humans to plants, morphic loci. have shown a strong negative correlation with monomeric proteins varying to a greater extent Table 5 Relationship between heterozygosity and quaternary than dimers, and even more so when compared to structure of various enzymatic and structural proteins trimers and tetramers (table 5).Koehnand Eanes (1979) noted that the mean heterozygosity per Q uaternary locus for enzymes with virtually identical average structure Man* Plaice** Range*** sub-unit molecular weight, decreases with increas- Monomers 0-096 0-164 0-113-0-186 ing structural complexity. These investigators also Dimers 0-071 0-132 0-040—0-122 compared the variability among the following three Tetramers 0-050 0-057 0-015-0-026 enzyme groups: (1) all monomeric enzymes, (2) * Harriset at, 1977 single-locus multimeric enzymes + multilocus **Wardand Bardmore, 1977 multimeric enzymes which do not form hybrid °'Rangeof averages for 23 invertebrate and 23 vertebrate molecules, and (3) multilocus multimeric enzymes species; Koehn and Eanes, 1979 350 C. LIVSHITS AND E. KOBYLIANSKY Pierce and Mitton (1980) similarly found a very combination in populations (species) with a high strong and significant negative correlation between level of heterozygosity. Lande (1984), for example, H (and particularly P) and the total amount of investigated by mathematical modeling the condi- nuclear DNA in various species of salamander. tions of maintaining the genetic correlations This finding is in line with Nevo's (1984) generali- between two polygenic characters. He concluded sation for numerous species, that genetic diversity that, even when selection favours a hgh genetic (H and P) is higher in species with a smaller correlation between the characters, with random diploid chromosome number. Thus these data mating and no linkage between loci influencing clearly indicate that where potential conditions different traits, the genetic correlation between exist for a high interlocus variability, the intralocus characters is likely to be small in magnitude. A variability tends to be low. genetic correlation of large magnitude can be (b) Organismic and taxonomic evidence Nevo and maintained only if the loci influencing different colleagues (1984) compared hundreds of species characters are tightly linked, or if there is a high and thousands of populations from different taxa level of inbreeding in the population. Because in with respect to 21 biotic variables and reached the parthenogenetic species fertilisation does not following conclusions: (1) The levels of genetic occur, e.g. they produce genetically highly inbred diversity vary non-randomly among populations, offspring, one would expect them to display a high species and higher taxa; (2) Mean values of both level of heterozygosity. Indeed, the evidence indi- polymorphism and heterozygosity decrease in cates that these populations commonly possess the following order: Invertebrata> Plants> elevated levels of heterozygosity in comparison Vertebrata; (3) Among invertebrates, crustaceans with cross-fertilised populations of the same and insects display the lowest values of H and P. species (Saura et aL, 1977; Lokki and Saura, 1980; The vertebrates showing the lowest mean values Vrijenhoek and Lerman, 1982). In general, of H and P were mammals; (4) All species, but parthenogenetic species exhibit a significantly especially mammals, present a distinct right skew- higher heterozygosity level than do primary out- ness of the H and P distribution; (5) Genetic crossing (i.e., sexual) species (H=0.301 vs. 0069; diversity is higher in species with small body size, p <001) (Nevo et a!., 1984). The parthenogenetic in numerically large species with a patchy popula- species as a rule are polyploids, but even diploid tion structure and limited migration, and in solitary parthenogenetic races have a higher H than do species. bisexuals. For example, in the insect population From the first four conclusions it would seem of Polydrosus molis, Lokki et aL (1976) found H that a decrease in diversity is related to an increase to be equal to 014 and 036 for the bisexual and in the morpho-physiological level of a taxon and parthenogenetic elements, respectively. this, in our opinion, reflects the level of complexity of an organism, whose functioning demands maximal harmony between its interacting parts. The first clause of the fifth conclusion is also in CONCLUSIONS agreement with this. As for the large-numbered species, they should have a large Ne and therefore 1.There are numerous genetic data from such a high H and P. From Nevo's review, however, it diverse taxonomic groups as plants, inverte- is clear that higher intralocus heterozygosity is to brates and vertebrates, including humans, be encountered in solitary or slow-moving species. indicating that sets of loci interact. Such a It would thus seem that the spatial subdivision of relationship can be attributed to Lerner's con- a population must decrease genetic combination cept of developmental homeostasis, which in it and thereby counteract the growth of inter- maintains that the higher the level of heterozy- locus genetic variability. However, the intralocus gosity the greater the extent of the buffering diversity in this case can increase. against insults by the external and internal As we have attempted to point out, the creation environment. of multiple internally coadapted heterozygous 2. Situations exist in which there is a breakdown genotypes acts against the maintenance and pre- of developmental homeostasis and general servation of such complex genotypes during free decrease in the fitness. Such breakdown can be recombination as a result of cross-fertilisation. We provoked by the intermixing of populations therefore suggest instead either a relative neutrali- within a species as a consequence of general sation of differences between alleles or the incompatibility between gene complexes existence of specific mechanisms preventing a re- coadapted within each population. HETEROZYGOSITY IN NATURAL POPULATIONS 351
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