Inbreeding and genetic disease in Sottunga, Finland

AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY 75:477-486 (1988)

In breeding and Genetic Disease in Sottunga, Finland ELIZABETH O’BRIEN, LYNN B. JORDE, BJORN RONNLOF, JOHAN 0. FELLMAN, AND ALDUR W. ERIKSSON Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84132 (E.O., L.B.J.); Hallbrink 11, SF-21600 Pargas, Finland (B. R); Samfundet Folkhalsans Genetiska Institut, 00101 Helsinki 10, Finland (LB.J., J.O.R, A. WE.); Institute of Human Genetics, Faculty of Medicine, Free University, 1007 MC Amsterdam, The Netherlands (A. WE.)

KEY WORDS Autosomal recessive diseases, Pedigree structure

ABSTRACT The contribution of inbreeding to the prevalence of recessive genetic diseases in the Aland Island parish of Sottunga is investigated. Ge- nealogical data for 3,030 individuals spanning up to 15 generations were used to estimate inbreeding. This small island community shows a low average inbreeding value of .0031 for the period 1725-1975. A cohort analysis shows that inbreeding increased from 1750 to 1900, when maximum inbreeding for those born in Sottunga reached .0057. A sharp decline in inbreeding occurred thereafter. Individuals with island-born parents made the largest contributions to inbreeding in all time periods compared to those with one or two migrant parents. These trends are consistent with changing migration patterns and isolate breakdown in Aland since 1900. An analysis of pedigree development demonstrates that remote consanguinity contributed more to inbreeding through time than close consanguinity. Both the number of common ancestors and the number of paths of relationship between spouses increased dramatically through time, the latter at a much faster rate. The contribution to average inbreeding per path, however, diminished rapidly through time. This analysis indicates that inbreeding does not account for the high incidence of autosomal recessive disorders, such as tapetoretinal disease, found in the parish.

Interest in the population genetics of the Aland Islands has its origin in von Wille- brand’s discovery of a rare bleeding disorder among members of three related families on one of the remote islands (von Willebrand, 1926). Since then, investigations of the distribution of von Willebrand disease in Aland have disclosed high frequencies of this autosomal dominant disorder in conjunction with high frequencies of other genetic disorders that appear rarely elsewhere. In larger Eu- ropean populations, von Willebrand disease affects one in 20,000 individuals (Biggs, 1983). It occurs with frequencies > 10% on some of bland’s smaller, remote islands and as high as 20% in the parish of Sottunga (Lehmann et al., 1980; Forsius et al., 1980). Other autosomal dominant disorders, including three additional types of hemostatic defects, are also prevalent in Aland (Eriksson

et al., 1980). Of direct interest to the present study are the several rare autosomal recessive diseases that occur with high frequency in the bland archipelago. For example, 26 cases of tapetoretinal disease were documented among the outer island population, which numbered 1700 in 1960 (Forsius et al., 1980).

In previous analyses of genetic diseases in Aland, extensive pedigrees have been assem- bled to demonstrate relatedness among families with affected individuals. It has been suggested that the high incidences of autosomal recessive disorders might be due to inbreeding (Forsius and Eriksson, 1970; Er- iksson, 1980). The mainland Finnish population also experiences high frequencies of a

Received June 1,1987; accepted August 31,1987.

0 1988 ALAN R. LISS, INC

478 E. O'BRIEN ET AL

number of otherwise rare recessive genetic diseases. Some have attributed this to genetic drift as opposed to inbreeding (Nevan- linna, 1972; Norio et al., 1973). Some clarification is in order here, however, since the random component of inbreeding, the portion of inbreeding due to random mating in a finite population, is in fact the same process as genetic drift (Allen, 1965; Crow and Kimura, 1970).

This study is an analysis of total inbreeding (i.e., both random and nonrandom inbreeding) on one of the small, remote islands of the archipelago, Sottunga. Drawing upon genealogical data, estimates of inbreeding through time are presented, with detailed analyses of the pedigree structure from which these estimates are derived. The focus of this analysis is twofold. First, the development of inbreeding in a small and fairly isolated population is characterized in detail. The extensive genealogical resources available in Aland for each parish provide a rare oppor- tunity to estimate the effects of remote inbreeding as well as of recent consanguinity. Second, the results of the inbreeding analysis are applied to clarify the origin of the prevalence of genetic disease in Aland.

BACKGROUND

Sottunga is one of 16 Lutheran parish sub- divisions that have been treated in previous studies of Wland's population structure, de- mography, and regional genetic variation (Eriksson et al., 1971a-c; Mielke et al., 1976, 1982; Workman and Jorde, 1980; Carmelli and Jorde, 1982; Jorde et al., 1982). More detailed descriptions of Aland's population can be found in those papers; relevant details are recapitulated only briefly here.

The Aland Islands are known to have been inhabited since about 5,000 BC, and the Swedish origins of the island population are known from archeological and linguistic af- finity as well as from written records dating to the 14th century (Ericksson, 1980). Per- manent settlement in the more remote outer islands dates to the 12th century, and population estimates indicate a densely settled peasant population until the 18th century. A bottleneck occurred at the beginning of the 18th century, when the Great Northern War reduced the population of over 10,000 to about 5,200 by 1721. These individuals are considered to be the founders of the contemporary Aland native population.

Eleven of bland's 16 parishes are on or near the main island, and five are dispersed among the outer islands of the archipelago. From 1750 until 1900, migration from outside Aland remained low, about 2.5%, and parish endogamy remained high, as much as 86%. After 1900, migration increased among the islands and between the islands and Fin- land and Sweden, bringing about a general decrease in isolation. In addition, the outer islands have been depopulated since 1900 as individuals relocated in urban centers. Aland's single urban center, Mariehamn, was incorporated at about that time, and today over 40% of Aland's population lives there (Mielke et al., 1976).

The demographic, genetic, and migration characteristics of Aland and the progress of isolate breakdown are not identical among parishes. Migration matrix and genetic dis- tance analyses have shown greater gene flow among main island parishes than among outer island parishes and greater genetic dif- ferentiation among the remote parishes (Mielke et al., 1976; Workman and Jorde, 1980; Jorde et al., 1982). Sottunga was shown to have the lowest endogamy rates over a large portion of the time period 1750-1950. Excluding individuals not born in Aland, Sot- tunga was also shown to have the most diver- gent gene frequencies of any parish (Mielke et al., 1976). Others have shown that, although Sottunga received few immigrants from Aland's other parishes, immigrants from Sweden and Finland came in numbers that effectively offset drift effects on gene frequencies after 1900 (Jorde et al., 1982; Car- melli and Jorde, 1982). Including immigrants from outside Aland, Sottunga's gene frequencies were shown to be similar to Aland's main island region by 1929. At that time, more than 20% of Sottunga's spouses had come from Sweden and Finland (Jorde et al., 1982).

MATERIALS AND METHODS

Sottunga's Lutheran parish registry pro- vided the main source of information from which genealogies were constructed by one of us (B.R.), an island native. The registries designate dates and locations of birth, marriage, and death. The genealogies were com- piled by working back in time from the contemporary population of about 250 individuals; the data now consist of a total of 3,292 individuals and over 800 nuclear families. The genealogical information spans

INBREEDING AND GENETIC DISEASE IN FINLAND 479

three centuries and up to 15 generations for some individuals. Vital information from the parish registries is considered fairly complete since at least 1750 (Mielke et al., 1976). Of the 3,292 individuals, 1,860 were born on Sottunga between 1690 and 1986.

The inbreeding coefficients for each individual were estimated using the full depth of an individual’s known pedigree. Closer analysis of trends through time were made by cohort division and again by comparing average values through time for individuals born on the island as opposed to those who migrated to Sottunga from elsewhere. In addition, the data were subdivided according to the migration status of parents, i.e., whether both, neither, or one was Sottunga-born. The contributions of each parent migration class to inbreeding through time were anlayzed. The relative contributions of close and remote consanguinity to inbreeding were eval- uated by calculating the number of unique common ancestors, total pedigree paths through a n ancestors, and per path contributions to F for inbred individuals.

RESULTS Unless otherwise stated, the following

analyses are based on 3,030 individuals; 262 were excluded because their birth years were unknown. In the analyses that follow, “inbred” individuals refer to those having one or more ancestors common to the mater- nal and paternal sides of their pedigree. Fig- ure 1 shows the distribution of the total population and the inbred portion of it by 25- year cohort. Cohort sizes increased until 1825 and sharply declined after 1875, demonstrat- ing the effects of emigration. The inbred portion of the population (N = 660) follows roughly the same pattern, with a less dramatic incline and a slightly later maximum. In Figure 1 (and in those that follow) post- 1950 values are based on a dramatically reduced cohort size of three births. This figure demonstrates the considerable aging of the outer island populations as younger individuals have sought economic opportunities elsewhere.

Following the same cohort scheme of Fig- ure 1, Figure 2 shows average inbreeding values for the total population and for those born on Sottunga. The graph shows a general increase in inbreeding for both classes from 1750 until 1900, when peak inbreeding reaches .0039 and .0057 for the total popula-

tion and for those born on Sottunga, respec- tively. Inbreeding declines precipitously thereafter, even as birth cohorts decline in size. The average inbreeding value for the total population over all time periods is .0021, and for those born on Sottunga it is slightly higher, .0031. The decline of inbreeding on Sottunga depicted in Figure 2 is consistent with the pattern of isolate breakdown through Aland, which began about 1900.

To explore further the effects of migration patterns on inbreeding, the temporal evalu- ation was extended to include parental migration histories. The population was divided according to four parent migration categories: 1) neither parent born on Sottunga, 2) father alone born on Sottunga, 3) mother alone born on Sottunga, and 4) both parents born on Sottunga. The number of individuals in each parent migration class and the average inbreeding coefficient for each class were calculated for each 25-year cohort. Figure 3 shows the distribution of all individuals according to their parental migration status. The largest class of individuals in earlier time periods is the “father alone” class and in later time periods the “both parent” class. Figure 4 shows the distribution of inbreeding among parental migration classes. From Fig- ure 4 it is clear that the individuals whose parents were both born on Sottunga account for the vast majority of inbreeding in every time period. Of particular note is that the “father alone” class barely contributes to inbreeding in any time period and the “mother alone” class only prior to 1875.

Comparing the distributions of individuals (Fig. 3) and average inbreeding per class (Fig. 4) demonstrates two interesting points. Whereas the number of individuals in the “both parent” class increases steadily until 1875 and then declines, their contribution to inbreeding is fairly stable, with one notable peak for those born 1876-1900. The maximum contribution to inbreeding for this class occurs later than the peak class size suggest- ing that overall inbreeding is not merely a function of the number inbred. In addition, prior to 1875, the “father alone” class is larger in size than the “mother alone” class but contributes less to inbreeding.

The disparities in contribution to inbreeding among the parent migration classes are to some extent the result of differential pedigree information. Although spouses who were both born on Sottunga surely have a

480

I- 200 t h 150 S

100

50

0,

E. O’BRIEN ET AL.

--

--

-- . . * .

-- * . . . . . . . . * , , . . , .

Cohort

Fig. 1. Size of 25-year birth cohorts and numbers inbred, 1750-1975.

t 0.007

0.006

t 0.001 \

Cohor t

Fig. 2. Average inbreeding in each 25-year cohort calculated for all individuals and for those born on Sottunga.

higher probability of being related, their pedigree information is also more complete. In the case of differential contributions to F by the single parent categories, two explana- tions must be considered. First, there was the possibility that pedigree information was more limited for off-island wives if patro- nyms were sometimes unknown. The average number of known ancestors is indeed much greater for those born on the island

(70) than for those born off the island (three). However, for those born off the island, there is no difference between men and women in number of known ancestors. Alternatively, the “father alone” class might be less inbred than the “mother alone” class because of dif- ferences in mate choice between these moth- ers and fathers. If in the earlier cohorts women and off-island husbands were more closely related on average than men and off-

INBREEDING AND GENETIC DISEASE IN FINLAND

T a0

No. 150

100

50

0

Father

Mother

Bo th

1750 1775 1800 1825 lE50 1875 1900 1925 1950 1975

Cohort

Fig. 3. Numbers of individuals per parent migration class in each 25-year cohort.

- F

i 0.014

0.012

0.000 0'01 T I 0.006

0.004

1750 1775 1825 1850 1875 1900 1925 1950

Nei ther

Father

@j Mother I- Both - -1 1975

481

Cohort

Fig. 4. Average inbreeding per parent migration class for each 25-year cohort.

island wives, then the observed result is expected. This aspect of mate choice will be treated in a later investigation.

Table 1 reports the percent distribution of individuals among close and remote inbreeding classes through time. Table 1 is divided into 50-year cohorts, which give sufficient detail regarding the temporal pattern of the distribution. These figures demonstrate, first of all, that most members of each cohort are

not inbred. In the 1750 cohort, individuals fall into only two categories, those who are not inbred and those who are relatively highly inbred. Given shallow pedigree information, this distribution is expected. After the earliest cohort, the distribution of individuals into various inbreeding classes fills out as pedigrees gain depth. Before 1900, the increases in inbreeding are due to a dimin- ishing proportion of noninbred individuals

482 E. O'BRIEN ET AL.

120 T l o o t 80 i' 20

Ancestors 1 W".']

1750 1775 1800 l P 5 1850 1875 1900 1925 1950 1975

Cohort Fig. 5. Average number of common ancestors and

paths for inbred individuals in each 25-year cohort.

0.014

0.012

0.01

0.008

0.006

0.004

0.002

0 1750 1775 1800 1825 1850 1875 1900 1925 1950

(31 per Path I '

1975

Cohort Fig. 6. Average contribution of each path to F for

inbred individuals.

TABLE 1. Percent distribution of each birth cohort among designated levels of inbreeding

F 1750 1800 1850 1900 1950 Total

0 91 83 64 68 77 78 >0-.004 0 8 17 14 13 10 ,004-.008 0 3 7 4 5 3 ,008-,012 0 1 4 3 4 2 .012-,016 7 1 1 2 0 2 .016-,020 0 2 6 4 1 3 > .020 1 2 1 5 1 2


and growing proportions in higher inbreeding classes. By 1900, a decline in overall inbreeding is seen. The proportion of those not inbred increases as migration patterns change, and the proportions in higher inbreeding classes generally decline.

The values in Table 1 specify levels of inbreeding, but they do not demonstrate the means by which these levels were achieved. Figure 5 shows the average number of ancestors common to the parents of each inbred individual. In addition, the average number of paths through all common ancestors for each inbred individual is shown. As expected, Figure 5 shows that both the number of paths and the number of ancestors increases through time as pedigrees gain depth. What is perhaps surprising is the dispropor- tionate increase in the average number of paths compared to ancestors. These quan- tities provide measures of how the pedigrees develop in complexity through time as a result of consanguineous matings. Similar analyses of pedigree structure in other populations are not available for comparison. However, in 1950, when the parents of inbred individuals averaged 26 common ancestors and more than 100 different paths of relationship, it is clear that inbreeding coefficients resulted from highly complex pedigree structures.

The relationship between paths and ancestors described in Figure 5 is of particular interest when compared to the development of total inbreeding. The number of inbred individuals increased through time until 1875 and then declined. The maximum average inbreeding coefficient, however, occurred later (after 1900), when the number of inbred individuals had begun to decrease. Figure 5 suggests that inbreeding continued to increase somewhat after 1875 because of developing pedigree complexity despite dimin- ishing numbers of inbred individuals. Until 1850, the maximum number of common ancestors was 12. By 1950 the maximum was 41, although fewer than 25 pedigrees con- tained more than 20 common ancestors.

The graph in Figure 6 further elucidates the mechanisms by which inbreeding evolved in this population.-This figure shows the average coefficient, F, per individual path in the pedigrees of inbred individuals. For comparison, the overall average inbreeding coefficients for the same individuals are included. A rapid increase in the number of paths in the pedigrees of inbred individuals through

time is shown in Figure 5. A further charac- terization of those paths is shown in Figure 6, which demonstrates a very rapid decline in the average contribution of each path to F through time. Any path established at an early pgint in time will, of course, contribute less to F as the number of generations in the pedigree grows. However, the steady decline in the average contribution shows that more recent consanguinity (shallower paths) did not contribute as much to inbreeding as remote consanguinity. The associated trends in Figures 5 and 6 suggest that inbreeding after 1875 primarily was due to extensive complexity within pedigrees that developed con- tinuously from early time periods but that represent a small portion of the population.

DISCUSSION

The genealogical information from Sot- tunga presents a fairly unique view of the dynamics of inbreeding in the population. From pedigrees, we have documented a developing pattern of inbreeding through time and, more importantly, the mechanisms by which the observed levels of inbreeding were achieved. Sottunga’s population size never grew much larger than 300 individuals. Mi- gration studies suggested that the island was an isolate within Aland, and one analysis of gene frequencies (excluding immigrants) also suggested an outlier status for the island. Preferred endogamy throughout much of Aland until about 1900 suggested the possibility of extreme inbreeding in the small remote islands such as Sottunga and consequently high prevalences of autosomal recessive disorders.

Comparison between populations on the basis of inbreeding estimates does not always provide a meaningful assessment of similar- ity or difference between them: The reference populations are not the same, and pedigree data are rarely comparable. However, com- parisons among many populations provide a rough scale of inbreeding against which to consider a population average. This study has shown that the majority of Sottunga’s population was not inbred throughout three centuries of genealogical history. It is not surprising, therefore, that Sottunga’s total average inbreeding, .0021, is lower than that of many isolates, such as the Samaritan population (.0434; Bonne, 1963), the island population of Tristan da Cunha (.0374; Roberts, 1967), or the considerably larger Hutterite S-

484 E. O’BRIEN ET AL.

leut (0.216; Mange, 1964). Sottunga’s average inbreeding does, however, resemble post- 1900 estimates for southern European populations, where inbreeding was also higher in previous times and declined as migration caused the breakup of isolates (McCullough and O’Rourke, 1986). It is also similar to some other island populations, such as Scot- land’s Orkney and Colonsay Islands (Roberts et al., 1979; Sheets, 1980).

The present analysis of Sottunga has shown that immigration and emigration counter- acted the continuous build-up of inbreeding that might otherwise have occurred in the absence of new additions to the gene pool. Marriage migration in particular seems to have had a strong impact on inbreeding and on the island’s gene frequencies (at least after 1900). Given Sottunga’s small population size, it is possible that migration was largely a function of mate availability, but the association remains to be determined. The effect of a closed pedigree structure on inbreeding has been demonstrated in the Tristan da Cunha population (Roberts, 19671, among whom limited mate choices and very little immigration resulted in a slow increase of inbreeding through time.

Relethford (1986) has shown in historical Massachusetts that population growth can depress the rate of accumulated inbreeding in a population. He has also demonstrated that long-range migration reduces the effect of past accumulated inbreeding. In Tokelau (Ward et al., 19801, even limited population growth made available more unrelated mate possibilities and arrested the build-up of inbreeding, and after five generations, a stable population average was reached. However, the association between population growth and inbreeding depends on factors of mate preference in conjunction with availability. Among isolated communities of the Upper Appennines in Italy, for instance, population growth and inbreeding were positively cor- related from 1750 until about 1920. In that region, the increase in inbreeding was inter- preted to be a result of increased cousin marriages contracted, in part, to preserve wealth within families (Pettener, 1985). In Sottunga, cohort sizes increased together with inbreeding until 1850, after which the two variables show less similar trends. Migration after 1900 in Sottunga prevented further increases in inbreeding by introducing new ancestors.

An individual whose parents are related at the third cousin level has an inbreeding coefficient of .0039 and pedigree information (at least) four generations deep. Forty-seven percent of those inbred in Sottunga have inbreeding coefficients due to consanguinity more remote than that of third cousins, a proportion that does not include some of the larger inbreeding coefficients due to multiple remote relationships. The importance of remote inbreeding, demonstrated by Sottun- ga’s genealogies, was documented many years ago in the Ramah Navajo population (Spuhler and Kluckhohn, 1953). In that population, a relatively low average inbreeding coefficient (.008) was estimated from pedigrees eight generations deep. Nearly 60% of the Ramah Navajo average was due to consanguinity at the third cousin level and beyond. Similarly, Roberts (1969) demonstrated a 50% difference in the impact of inbreeding on estimates of genetic load in Tristan da Cunha when paths of relationship beyond the nearest degree were considered.

One of the primary reasons for undertak- ing this study was to determine whether inbreeding could account for the high levels of recessive diseases observed in Sottunga and other outer island parishes. Consider a rare recessive disorder that affects 1110,000 individuals (q2 = .OOOl> in the absence of inbreeding. If f = .005 the expected genotype 5 frequency becomes q (1 - f) + qf = .00015, or approximately 116,700 affected individuals. Even if the gene frequency is high (q = .05), an inbreeding level of .005 increases the expected frequency of affected individuals from 11400 to only 11365. Thus the observed frequency of recessive tapetoretinal disease, greater than 1/65 individuals in the outer islands, is unexpectedly large at any level of inbreeding comparable to that observed in Sottunga.

It seems likely that the effects of small population size and drift, or random inbreeding, rather than nonrandom inbreeding, are responsibIe for the high frequencies of recessive diseases seen in Sottunga. This conclusion is supported by the apparently low nonrandom component of the total inbreeding value reported here and by two additional lines of evidence. First, previous analyses of gene frequencies in Aland showed that the outer island parishes had relatively high levels of genetic variation (Fst = 0.014) because of small population sizes and isola-


tion (Jorde et al., 1982). These results impli- cate drift as an important mechanism in some of the parish populations. Second, the extraordinarily high frequencies of von Wil- lebrand disease in the outer islands must be due to founder effects and drift, since this is an autosomal dominant disorder.

In this study, the random (because of finite population size) and nonrandom (because of mate choice preference) components of inbreeding have not been measured separately. Together, these aspects of inbreeding suggest a minor effect on elevating frequencies of autosomal recessive diseases in bland. How- ever, it remains to be understood whether inbreeding in Sottunga is close to that expected by random mating or whether avoid- ance of consanguineous mating accounts for low inbreeding on the island. This question will be treated in a subsequent investigation.

It must be emphasized that our estimates of inbreeding, like all such estimates from genealogical data, are undervalued. Error in these estimates stems from two sources. First, though comparatively deep, the pedigree information extends for a limited number of generations. Since the pedigree data are substantial only from about 1700, the “founders” of Sottunga are not a collection of unrelated individuals, as assumed by classi- cal models. Instead, some founders were probably related to one another and may have already carried multiple copies of the disease genes of interest. Second, pedigree information for immigrants is lacking, so that most of them are assumed to be unrelated to their island-born spouses. However, many of these immigrants came from neigh- boring parishes, some of which undoubtedly shared ancestors (and disease genes) with Sottunga’s population. Both these considera- tions are important to an understanding of present-day disease prevalence in Sottunga resulting from past generations of random and nonrandom inbreeding.

This study has demonstrated how population genetic analyses can help to explain the distribution and prevalence of genetic disease. A direct analysis of inbreeding among individuals affected by autosomal recessive diseases will be the subject of future studies.

CONCLUSIONS

This analysis depicts the evolution of inbreeding in the small bland Island parish of Sottunga. In general, inbreeding increased

steadily from 1750 until just after 1900, when changes in migration patterns reduced isolation, reduced the population size, and de- creased inbreeding. The Sottunga pedigrees suggest low estimates of overall inbreeding (F = .0021) for a small island population because of both immigration and emigration. The great disparity in the relative contributions of migrants vs. nonmigrants to inbreeding clearly demonstrates the mitigating effects of migration on inbreeding in this population. The dramatic build-up of remote consanguinity shown in the analysis of path and ancestor contributions demonstrates the substantial impact of pedigree depth and complexity on estimates of inbreeding. However, in Sottunga, migration limited those effects as developing pedigrees were truncated and new ancestors introduced. Finally, the high incidence of some autosomal recessive disorders in Sottunga is likely the result of founder effects and drift rather than nonrandom inbreeding. The excessive frequencies and similar distributions of autosomal dominant disorders, such as von Willebrand disease, further substantiate this conclusion.

ACKNOWLEDGMENTS

Inbreeding coefficients were calculated using a computer algorithm written by Dr. An- thony Boyce, adapted and modified by Dr. Richard Kerber. We thank Dr. James Mielke, Kari Pitkanen, and two anonymous review- ers for helpful comments on this work. Dr. Alan Rogers’ insightful criticisms of the manuscript are much appreciated. This re- search was supported by NSF grant BNS- 8319448 and by grants from the Sigrid Juse- lius Foundation, Helsinki.

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Inbreeding and genetic disease in Sottunga, Finland

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