INBREEDING IN HUMANS

Eugene Ochap

Genetics 535

3-22-04

Inbreeding is simply defined as the mating of relatives. It is a mating system in which individuals carry alleles that originated from a common ancestor. Inbreeding is considered a problem in humans because inbreeding increases the chances of receiving a deleterious recessive allele inherited from a common ancestor. When discussing inbreeding, the level at which is taking place becomes important. Most studies are concerned with close inbreeding, also known as incest, which usually sets a threshold at the level of first-cousin mating (Thornhill 1993).

When discussing inbreeding, one of the most important values to be concerned with is the inbreeding coefficient. The inbreeding coefficient represents the probability that an offspring will receive a gene from each parent that is a copy of a single shared ancestral gene. The inbreeding coefficient is zero if the parents do not share a common ancestor, and if the inbreeding coefficient is one than the offspring has a 100% chance of receiving two copies of the ancestral gene. However, this maximum inbreeding coefficient of one cannot be achieved in human populations (Dorsten 1999).

In western civilization consanguineous marriages and human inbreeding have been frowned upon by society for some time now. In fact, statutes passed in the 19^th and early 20^th centuries made inbreeding and marriages to the first cousin level illegal in the majority of the United States. The earliest recorded study of inbreeding and its effects on human health was reported by Bemiss in 1858. Charles Darwin became very interested and upset at this idea that children of consanguineous marriages could be biologically disadvantaged. These uneasy feelings towards these new reports were due to the fact that Darwin married his first cousin, Emma Wedgewood, and the two gave birth to ten children (Bittles 1991). In 1970, Darwin continued his opposition to this issue by stating

"… In England and many parts of Europe the marriages of cousins are objected to from their supposed injurious consequences: but this belief rests on no direct evidence. It is there manifestly desirable that the belief should be either proven false, or should be confirmed, so that in this latter case the marriages of cousins might be discouraged…" (Hedrick 1991).

Darwin then attempted to provide evidence to support his point of view. In 1871, Darwin attempted to get questions concerning numbers and effects of cousin marriages included in the census of Great Britain and Ireland. The request for the inclusion of these questions into the census was declined, but Darwin's son George came up with a new approach to studying inbreeding in humans. He came up with an approach, which is still used in some studies today, known as martial isonomy that uses surnames to estimate numbers of consanguineous marriages. To look at the physical effects of inbreeding, George Darwin examined the incidence of first cousin progeny among oarsmen on the teams at the University of Oxford and the University of Cambridge. Although, these historical studies provided little information concerning the incidence of inbreeding and its effects on humans, they did pave the way for some more important future studies (Bittles 1991).

REASONS A POPULATION WOULD PRACTICE INBREEDING

Due to concerns surrounding inbreeding and its effects, levels of inbreeding dropped as low as 0.5% in the 1990s at the first cousin level in the general populations North America and Western Europe, and the levels were even lower in Japan. Even though inbreeding levels have decreased in western civilizations, many studies have shown that in many other large societies consanguineous marriages still predominate. In fact, in many large populations of Asia and Africa twenty to fifty percent of all unions are that of consanguineous marriages (Bittles 1991). There are several circumstances that would give a population a reason to practice inbreeding at a large scale. Some of these reasons for practicing inbreeding include royalty, religion and culture, socioeconomic class, and geographic isolation and small populations.

Religion and culture can play a large role in the amount of inbreeding that takes place in a population. In many Muslim and Hindu societies in Africa, Asia, and India, consanguious marriages, especially unions of first cousins, account for twenty to fifty-five percent of the total. These religions tend to inbreed because of religious acceptance, preference, and tradition. Moreover, the culture of these societies also plays a large role into increased levels of inbreeding. Consanguineous marriages are thought to be an advantage when considering compatibility of the bride and her husband's family. This is particularly important when discussing the bride's relationship with her mother-in-law and the up-keep of the family's property. Another incentive to close relative marriages concerns bride wealth and dowry. Consanguineous marriages can lead to greatly reduced or no payments at all in unions of this culture. This allows small landowning families to keep their property and land (Bittles 1991).

Other groups that are associated with inbreeding because of religion and culture are the small Anabaptist populations in North America. These groups include the Amish, the Mennonites, and the Hutterites. These groups settled in North America in the 18^th and 19^th centuries in search of religious freedom. These populations have shown increases in consanguineous marriages over time, and the high was reached in the 1950's when some groups reached levels of consanguineous marriages as high as 85%. The reason for the high levels of inbreeding is not only due to religion; it can also be attributed to the small isolated farming communities in which these populations find themselves. These factors of religion and small communal societies lead to limited choices when searching for possible mates (Agarwala 2001).

Geographic isolation and population size play a large role in many populations when concerning levels of inbreeding and genetic barriers. Migration rates can also play a large role in inbreeding levels. Furthermore, as the number of generations since the isolated population was founded increases so should the inbreeding levels. Several of these factors were seen in studies in small communities and countries located and isolated in European mountain ranges. One such population study was performed in the country of Andora. Andora is on of the smallest countries in Europe, and it is very isolated by being surrounded by very high mountains in the Central Pyrenees. It was traditionally a small agricultural and cattle farming country that had a population between 4,000 and 6,000. This was an ideal model for high inbreeding levels, but changes in the economy has caused a decline in these levels over the past fifty years. The economy of Andora has grown to include areas of tourism and trade, and immigration has increased to Andora partially due to the absence of taxes and beautiful scenery. The population has grown to approximately 46,000 people, which itself can cause a decline in inbreeding levels because it increases the number of mates to choose from and brings new views and ideas to the population (Gonzalez-Martin 2002). Another isolated population study that has seen a decrease in consanguinity levels is located in the Gredos Mountain Range in Spain. The inbreeding levels decreased over time, and it was thought to be due to industrialization, greater population movement, a decrease in family size, and an increase in literacy rates. These studies show that inbreeding levels can depend largely on geographic, demographic, social, and economic factors (Fuster 2001). Furthermore, numerous other studies have shown that socioeconomic status can have a large impact on the level of inbreeding. In many cases the poorest and least educated members of a community tend to have the highest inbreeding levels in a population.(Bittles 1991).

Inbreeding has also been seen to occur frequently in many royal families' histories. Royal incest was commonly found in Ancient Egyptian, Incan, Hawaiian, and many European royal families. Brother-sister unions become more frequent when royalty is the major factor concerning the incidence of inbreeding. There are several factors that can explain why royalty leads to high levels of inbreeding. One factor is that the king has limitless power in many cultures, and he can do what he wants and marry who he wants. Also, in many cases inbreeding is practiced in royal families to preserve royal blood lines. Another explanation is that a royal family can keep land, material possessions and resources within the family. Moreover, brother-sister royal incest allows succession of the throne to both a male and female blood line. There are also cases in which royal incest is part of a culture and is sometimes linked to legends or myths. One of the best documented cases of this was seen in the Incan culture in the 16^th century. The Incan king was to marry his full sister. This was done to emulate the king's mythical ancestor, the Sun, who married his sister, the Moon, and this was thought to preserve the purity of the divine royal blood line (Van Den Berghe 1980).

Royalty also uses inbreeding to try to maximize fitness. One of the royal strategies to maximize fitness by using inbreeding to put as close to a genetic clone as possible on the throne as the heir. Moreover, females tend to maximize fitness by picking the best possible mate, which in this case would mean marrying to a higher social class. This leads to women with the highest-status in a population to being the most inbred in this type of society (Van Den Berghe 1980).

EFFECTS OF INBREEDING

The negative health effects caused by inbreeding are due to the expression of rare, recessive deleterious genes that are inherited from common ancestors or a single shared ancestor. Studies on population in which inbreeding is common have shown increased levels of mortality and morbidity due to a variety of genetic defects. However, inbreeding can also result in the production of perfectly healthy offspring (Bittles 1991).

Study of European Royal Families

Inbreeding was very common among the royal families of Europe, and it has been linked as the cause of the widespread number of cases of hemophilia in the families. The presence of hemophilia in the royalty of Europe started with Queen Victoria of England. Victoria is thought to be the original carrier for the recessive X-linked hemophilia gene, which lead to over twenty members of royal families inheriting the disease in just over 100 years. The disease was spread throughout Europe, because Queen Victoria's children and grandchildren married into many different royal houses in Europe to create political alliances. Females can only been carriers for the rare blood clotting disease if one of there X chromosomes contains the deleterious recessive allele. Moreover, males inherit the disease if there X chromosome carries the gene for hemophilia.

Hemophilia spreads rapidly through the British royal house for several generations, and inbreeding in the family was seen as a major cause of the deleterious recessive allele's frequently through the lines of British royalty. Moreover, the disease was also spread into the royal houses of Russia and Spain by descendants of Queen Victoria. Victoria gave birth to three children with the hemophilia allele; Leopold, Alice, and Beatrice. Alice then gave birth to two female carriers and one male hemophiliac. One of the carrier daughters was Alexandra, also known as Alix. Alix was married to Nicholas the Czar of Russia in 1894. Alix then had tremendous pressure on her to produce a male heir. She finally gave birth to a male, Alexis, but he had hemophilia. This lead to political unrest in Russia, and the royal family was executed by a firing squad during the Russian Revolution.

Hemophilia was also spread into the Spanish royal family when Victoria Eugenie, a hemophilia carrier and daughter of Beatrice, married Alfonso XIII, the king of Spain. The marriage was arranged to try to bring Spain and England closer together. This attempt did not work when Beatrice gave birth to two sons with hemophilia. This event led to increase anti-British feeling in Spain, because many believed that the Spanish monarchy's blood line was polluted by this British Princess.

The events in Russia and Spain along with an increase in British hemophiliacs led to political unrest and instability. Many people believe these cases of inbreeding and hemophilia to be a contributing cause to World War I. Moreover, a mystery surrounds the originator of the hemophilia gene in England. No ancestor of Queen Victoria showed any evidence of hemophilia, so several theories arose on the gene's origin. One theory is that Victoria was the victim of a mutation that could have been due to years of inbreeding in British royalty. Another interesting theory is that Victoria's mother had an affair because of the intense pressure of producing an heir, and the Edward Duke of Kent was not Victoria's biological father (Stevens 1991).

Study on Japanese Children after WWII

Shortly after the United States dropped two atomic bombs on Japan in World War II there was an increase in the number of consanguineous marriages in the areas surrounding Hiroshima and Nagasaki. The most common union was seen to be inbreeding at the first-cousin level. The study was set up to study some of the possible effects of inbreeding. The five effects of inbreeding looked at in this study was: the fertility of the marriages, the mortality of the offspring, the morbidity of the offspring, the reproductive performance of the offspring, and the characteristics of the offspring.

In the study it was seen that inbreeding did not have an adverse effect on the fertility of the marriages, but there were some significant increases seen on childhood mortality in the first year of life. Inbreeding also increased morbidity in the study. There were significant increases in levels of handicapped offspring associated with inbreeding. Inbreeding was associated with a 37.5% increase in offspring with one or two major handicaps, while it also caused a 24.1% increase in offspring with one or two minor defects. Moreover, inbreeding caused an increase of 31.7% in hearing impairments. Development also seemed to be affected by inbreeding. Children of consanguineous marriages were significantly older than the control group when they first walked and talked.

The study did not only show harmful effects of inbreeding in Japan. School performance, which is a vital part for betterment in their culture, showed no significant change with inbreeding. In fact, intelligence seemed to be more influenced by socioeconomic class. Furthermore, inbreeding also seemed to be beneficial when examining some aspects of health. Offspring from the inbreeding group showed a 14.3% decrease in allergies and a 23.9% decrease in nephritis, a rare genetic disorder that causes inflammation of the kidneys (Schull 1965).

Study on an Amish Settlement

The Old Order Amish tend to have high levels of inbreeding, because they are a highly traditional agricultural and religious group that is very isolated from outside populations. These high levels of inbreeding are seen in a settlement in Lancaster, Pennsylvania. Moreover, this group is a good study group because they come from similar backgrounds and socioeconomic class. They also keep very detailed genealogical records. These records date back to the 1700s and show a family history for up to twelve generations.

Inbreeding in the Lancaster settlement is thought to be a major cause of infant mortality due to genetic defects. One of these deleterious recessive genetic disorders that led to increased infant mortality is Ellis-van Creveld disease. Ellis-van Creveld is a disease associated with dwarfism in the extremities and a malformation in the heart's atrium. These genetic problems have been seen to be the reported cause for almost all of the deaths of children under the age of one in the Lancaster settlement. Therefore, it was seen that inbreeding increased the likelihood of early childhood deaths in the Lancaster Amish settlement. In fact, the higher the level of inbreeding coefficients involved in the marriage, the greater the chances of cases of childhood mortality. This study shows that inbreeding can pose significant health threats by increasing mortality and morbidity in offspring (Dorsten 1999).

Study on the Hutterites

The Hutterites are a small group of Anabaptists that fled Europe and Russia and settled in what is now the Dakotas and Canada to escape from religious persecution. The Hutterites settled on communal farms, which isolated them from outside populations. Their isolation along with their beliefs leads to a highly inbred population. Moreover, the Hutterites are a good population to study because, like the Amish, they keep very detailed genealogical records. The Hutterites are also among the most fertile populations that commonly practice inbreeding. Furthermore, in studies concerning the Hutterites the confounding effects of socioeconomic class are not a factor, because they are relatively uniform in this population's communal lifestyle. One such study wanted to investigate some of the effects of inbreeding on the fertility of adult women.

Little is known about the effects of inbreeding on offspring's fertility, so this study was done to answer some of these questions. There were several measurements used to detect any adverse changes in fertility. Inbreeding coefficients, measurements of birth intervals, and family size were all measured. The offspring of the Hutterite women showed that the intervals between births decreased as levels of inbreeding increased. These intervals not only increased as inbreeding levels increased, they also increased with each generation of Hutterite women. Therefore, the deleterious effects of inbreeding can be tracked through each generation. These significantly longer interbirth intervals were due to lower conception rates or higher losses in embryonic stages of pregnancy. Moreover, this also caused large declines in family size. In fact, average family size shrunk from above nine from 1901 to 1920 to five from 1941 to 1960. This showed a decrease in two family members per generation in the Hutterite population. This study has shown that deleterious recessive alleles received from inbreeding can lower the fertility rates of adult woman (Ober 1999).

Study on a Population in Dammam, Saudi Arabia

Dammam is the capital city of the oil-rich Eastern Province of Saudi Arabia. The population of Dammam is estimated to close to two-hundred thousand, and the rate of consanguineous marriages is around 52%, which is higher than the average rates of most countries and providences in the Middle East and the surrounding area. First-cousin marriages dominated all forms of marriage in Dammam accounting for 39.3% of the unions. The high rates of consanguineous marriages lead to a relatively high inbreeding coefficient of 0.0312. These high rates of inbreeding were thought to be due to beliefs, culture, and to keep property within the family.

A study was performed on the population from Dammam to see how inbreeding could affect certain aspects of offspring's health. The study first looked at "Reproductive wastage," which was defined as the number of stillbirths, childhood death's in the first month of life, and childhood deaths during the first year of life. This study showed no real significant differences in "reproductive wastage" between consanguineous and non-consanguineous marriages. Moreover, birth weights were also examined and no significant differences were seen between mean birth weights of children from consanguineous marriages and children from out breeding relationships. These results were somewhat different from other studies performed that showed inbreeding to have negative affects on offspring.

This study shows that inbreeding is not always harmful and can produce perfectly normal offspring. In fact, some investigators believe that long-term practice of inbreeding can actually benefit a population and its health by reducing deleterious or harmful genes (Al-Abdulkareen 1998). The reduction of these harmful genes is thought to be a result of an increased frequency of the deleterious gene's presence which can make it more vulnerable to selection. Therefore, selection could eliminate the harmful gene if it is given ample time to "act" on it (Hedrick 1991).

CONCLUSION

There are several reasons that a population would practice inbreeding that span from religion to geography to royal bloodlines. Many studies have shown that inbreeding can cause increases in mortality and morbidity. As populations become more knowledgeable to these possible effects levels of inbreeding tend to decrease. However, there are other populations that are less knowledgeable to the possible negative outcomes of inbreeding, and it is possible that the effects of inbreeding may not be detectable or visible. Therefore, if there are harmful recessive alleles present in the population, the genes and characteristics still have the possibility of surfacing and negatively affecting a population, but it is very possible that the population will never see any harmful effects due to incest. In fact, some experts believe that in some cases inbreeding can be helpful to a population by constantly exposing harmful recessive genes to selection. By frequently exposing these genes to selection, the harmful alleles can become permanently eliminated from the population. Inbreeding is a very touchy and controversial subject when it concerns humans, and there is still a lot that we do not know about the possible effects of inbreeding. It is very difficult to run experiments to determine all the possible effects of inbreeding in humans, because there are just too many variables to control. Moreover, ethics makes it difficult and many times impossible to perform studies on humans. However, most experts would agree that practicing outbreeding will provide a population with the best opportunity to achieve a high level of health.

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