Inbreeding

From Wikipedia, the free encyclopedia
Jump to: navigation, search

Inbreeding is the production of offspring from the mating or breeding of individuals or organisms which are closely related genetically, in contrast to outcrossing, which refers to mating unrelated individuals.1 By analogy, the term is used in human reproduction, but more commonly refers to the genetic disorders and other consequences that may arise from incestuous sexual relationships and consanguinity.

Inbreeding results in homozygosity, which can increase the chances of offspring being affected by recessive or deleterious traits.2 This generally leads to a decreased biological fitness of a population,34 (called inbreeding depression) which is its ability to survive and reproduce. An individual who inherits such deleterious traits is referred to as inbred. The avoidance of such deleterious recessive alleles caused by inbreeding is the main selective reason for outcrossing.56

Inbreeding is a technique used in selective breeding. In livestock breeding, breeders may use inbreeding when, for example, trying to establish a new and desirable trait in the stock, but will need to watch for undesirable characteristics in offspring, which can then be eliminated through further selective breeding or culling. Inbreeding is used to reveal deleterious recessive alleles, which can then be eliminated through assortative breeding or through culling. In plant breeding, inbred lines are used as stocks for the creation of hybrid lines to make use of the effects of heterosis. Inbreeding in plants also occurs naturally in the form of self-pollination.

Overview

Offspring of biologically related persons are subject to the possible impact of inbreeding, such as congenital birth defects. The chances of such disorders is increased the closer the relationship of the biological parents. (See coefficient of inbreeding.) This is because such pairings increase the proportion of homozygous zygotes in the offspring, in particular deleterious recessive alleles, that produce such disorders.7 (See inbreeding depression.) Because most recessive alleles are rare in populations, it is unlikely that two unrelated marriage partners will both be carriers of the alleles. However, because close relatives share a large fraction of their alleles, the probability that any such deleterious allele is inherited from the common ancestor through both parents is increased dramatically. Contrary to common belief, inbreeding does not in itself alter allele frequencies, but rather increases the relative proportion of homozygotes to heterozygotes. However, because the increased proportion of deleterious homozygotes exposes the allele to natural selection, in the long run its frequency decreases more rapidly in inbred population. In the short term, incestuous reproduction is expected to produce increases in spontaneous abortions of zygotes, perinatal deaths, and postnatal offspring with birth defects.8

There may also be other deleterious effects besides those caused by recessive diseases. Thus, similar immune systems may be more vulnerable to infectious diseases (see Major histocompatibility complex and sexual selection).9

Genetic disorders

Autosomal recessive disorders occur in individuals who have two copies of the gene for a particular recessive genetic mutation.10 Except in certain rare circumstances, such as new mutations or uniparental disomy, both parents of an individual with such a disorder will be carriers of the gene. These carriers do not display any signs of the mutation and may be unaware that they carry the mutated gene. Since relatives share a higher proportion of their genes than do unrelated people, it is more likely that related parents will both be carriers of the same recessive gene, and therefore their children are at a higher risk of a genetic disorder. The extent to which the risk increases depends on the degree of genetic relationship between the parents: The risk is greatest when the parents are close relatives and lower for relationships between more distant relatives, such as second cousins, though still greater than for the general population.11

Children of parent-child or sibling-sibling unions are at increased risk compared to cousin-cousin unions.12

Inbreeding may result in a far higher phenotypic expression of deleterious recessive genes within a population than would normally be expected.13 As a result, first-generation inbred individuals are more likely to show physical and health defectscitation needed, including:

Inbreeding can occur just because a small population has been isolated during some time, so that all breeding individuals became genetically related. It can also occur in a large population if individuals tend to mate with their relatives, instead of mating at random.

Many individuals in the first generation of inbreeding will never live to reproduce.14 Over time, with isolation such as a population bottleneck caused by purposeful (assortative) breeding or natural environmental factors, the deleterious inherited traits are culled.5615

Island species are often very inbred, as their isolation from the larger group on a mainland allows natural selection to work upon their population. This type of isolation may result in the formation of race or even speciation, as the inbreeding first removes many deleterious genes, and allows expression of genes that allow a population to adapt to an ecosystem. As the adaptation becomes more pronounced the new species or race radiates from its entrance into the new space, or dies out if it cannot adapt and, most importantly, reproduce.16

The reduced genetic diversity that results from inbreeding may mean a species may not be able to adapt to changes in environmental conditions. Each individual will have similar immune systems, as immune systems are genetically based. Where a species becomes endangered, the population may fall below a minimum whereby the forced interbreeding between the remaining animals will result in extinction.

Natural breedings include inbreeding by necessity, and most animals only migrate when necessary. In many cases, the closest available mate is a mother, sister, grandmother, father, brother, or grandfather. In all cases, the environment presents stresses to remove those individuals who cannot survive because of illness from the population.

There was an assumption that wild populations do not inbreed; this is not what is observed in some cases in the wild. However, in species such as horses, animals in wild or feral conditions often drive off the young of both genders, thought to be a mechanism by which the species instinctively avoids some of the genetic consequences of inbreeding.17 In general, many mammal species including humanity's closest primate relatives avoid close inbreeding possibly due to the deleterious effects.18

Examples

Although there are several examples of inbred populations of wild animals, the negative consequences of this inbreeding are poorly documented.

The cheetah has very low levels of genetic variation, suggesting a population bottleneck (of unknown cause) and subsequent inbreeding sometime in the past several thousand years.19 All cheetahs now come from this small gene pool. Theoretically, their lack of genetic variance could put cheetahs at greater risk from infectious diseases. One outbreak of feline infectious peritonitis in a captive cheetah population which was studied over a 5-year period had a morbidity rate of over 90%, and a mortality rate of 60%.20 Conversely, inbreeding can purge a population of deleterious alleles, and the cheetah is known for few genetic illnesses.

In the South American sea lion, there was concern that recent population crashes would reduce genetic diversity. Historical analysis indicated that a population expansion from just two matrilineal lines were responsible for most individuals within the population. Even so, the diversity within the lines allowed great variation in the gene pool that may help to protect the South American sea lion from extinction.21

In lions, prides are often followed by related males in bachelor groups. When the dominant male is killed or driven off by one of these bachelors, a father may be replaced with his son. There is no mechanism for preventing inbreeding or to ensure outcrossing. In the prides, most lionesses are related to one another. If there is more than one dominant male, the group of alpha males are usually related. Two lines are then being "line bred". Also, in some populations such as the Crater lions, it is known that a population bottleneck has occurred. Researchers found far greater genetic heterozygosity than expected.22 In fact, predators are known for low genetic variance, along with most of the top portion of the tropic levels of an ecosystem.23 Additionally, the alpha males of two neighboring prides can potentially be from the same litter; one brother may come to acquire leadership over another's pride, and subsequently mate with his 'nieces' or cousins. However, killing another male's cubs, upon the takeover, allows the new selected gene complement of the incoming alpha male to prevail over the previous male. There are genetic assays being scheduled for lions to determine their genetic diversity. The preliminary studies show results inconsistent with the outcrossing paradigm based on individual environments of the studied groups.22

In Central California, the Sea Otters were thought to have been driven to extinction due to over hunting, until a colony of about 30 breeding pairs was discovered in the Big Sur region in the 1930s. Since then the population has grown and spread along the central Californian coast to around 2000 individuals, a level that has remained stable for over a decade. Population growth is limited by the fact that all Californian Sea Otters are descended from the isolated colony resulting in inbreeding.

Measures of inbreeding

A measure of inbreeding of an individual A is the probability F(A) that both alleles in one locus are derived from the same gene in an ancestor. Two alleles derived from the same gene in an ancestor are said to be identical by descent. This probability F(A) is called the "coefficient of inbreeding".24

Another useful measure that describes the extent to which two individuals are relatives (say individuals A and B) is their coancestry coefficient  f(A,B), which gives the probability that, taking one random allele from A and another random allele from B, both are identical by descent. This is also denoted kinship coefficient between A and B.

A particular case is the self-coancestry of individual A with itself, f(A,A), which is the probability that taking one random allele from A and then, independently and with replacement, another random allele also from A, both are identical by descent. Since they can be identical by descent by sampling the same allele or by sampling both alleles that happen to be identical by descent, we have  f(A,A) = 1/2 + F(A)/2.25

Both the inbreeding and the coancestry coefficients can be defined for specific individuals or as average population values. They can be computed from genealogies or estimated from the population size and its breeding properties,but all methods assume no selection or are limited to neutral alleles.

There are several methods to compute this percentage. The two main ways are the path method26 and the tabular method.27unreliable source?

Typical coancestries between relatives are as follows:

  • Father/daughter, mother/son or brother/sister → 25% (14)
  • Grandfather/granddaughter or grandmother/grandson → 12.5% (18)
  • Half-brother/half-sister, Double cousins → 12.5% (18)
  • Uncle/niece or aunt/nephew → 12.5% (18)
  • Great-grandfather/great-granddaughter or great-grandmother/great-grandson → 6.25% (116)
  • Half-uncle/niece or half-aunt/nephew → 6.25% (116)
  • First cousins → 6.25% (116)

Domestic animals

An intensive form of inbreeding where an individual S is mated to his daughter D1, granddaughter D2 and so on, in order to maximise the percentage of S's genes in the offspring. 87.5% of D3's genes would come from S, while D4 would receive 93.75% of their genes from S.28

Breeding in domestic animals is assortative breeding primarily (see selective breeding). Without the sorting of individuals by trait, a breed could not be established, nor could poor genetic material be removed. Homozygosity is the case where similar or identical alleles combine to express a trait that is not otherwise expressed (recessiveness). Inbreeding, through homozygosity, exposes recessive alleles.

Breeders must cull unfit breeding suppressed individuals or individuals who demonstrate either homozygosity or heterozygosity for genetic based diseases.29 The issue of casual breeders who inbreed irresponsibly is discussed in the following quotation on cattle:

Meanwhile, milk production per cow per lactation increased from 17,444 lbs to 25,013 lbs from 1978 to 1998 for the Holstein breed. Mean breeding values for milk of Holstein cows increased by 4,829 lbs during this period.30 High producing cows are increasingly difficult to breed and are subject to higher health costs than cows of lower genetic merit for production (Cassell, 2001).

Intensive selection for higher yield has increased relationships among animals within breed and increased the rate of casual inbreeding.

Many of the traits that affect profitability in crosses of modern dairy breeds have not been studied in designed experiments. Indeed, all crossbreeding research involving North American breeds and strains is very dated (McAllister, 2001) if it exists at all.31

Linebreeding is a form of inbreeding. There is no clear distinction between the two terms, but linebreeding may encompass crosses between individuals and their descendants or two cousins.2832 This method can be used to increase a particular animal's contribution to the population.28 While linebreeding is less likely to cause problems in the first generation than does inbreeding, over time, linebreeding can reduce the genetic diversity of a population and cause problems related to a too-small genepool that may include an increased prevalence of genetic disorders and inbreeding depression.citation needed

Outcrossing is where two unrelated individuals are crossed to produce progeny. In outcrossing, unless there is verifiable genetic information, one may find that all individuals are distantly related to an ancient progenitor. If the trait carries throughout a population, all individuals can have this trait. This is called the founder effect. In the well established breeds, that are commonly bred, a large gene pool is present. For example, in 2004, over 18,000 Persian cats were registered.33 A possibility exists for a complete outcross, if no barriers exist between the individuals to breed. However it is not always the case, and a form of distant linebreeding occurs. Again it is up to the assortative breeder to know what sort of traits both positive and negative exist within the diversity of one breeding. This diversity of genetic expression, within even close relatives, increases the variability and diversity of viable stock.34

Laboratory animals

Systematic inbreeding and maintenance of inbred strains of laboratory mice and rats is of great importance for biomedical research. The inbreeding guarantees a consistent and uniform animal model for experimental purposes and enables genetic studies in congenic and knock-out animals. The use of inbred strains is also important for genetic studies in animal models, for example to distinguish genetic from environmental effects.

Humans

Possible increase of fertility

A study in Iceland by the deCODE genetics company, published by the journal Science, found that third cousins produced more children and grandchildren than more distant marriages, suggesting that "in spite of the fact that bringing together two alleles of a recessive trait may be bad, there may be some biological wisdom in the union of relatively closely related people".35 For hundreds of years, inbreeding was historically unavoidable in Iceland due to its then tiny and isolated population.36

Royalty and nobility

Inter-nobility marriage was used as a method of forming political alliances among elites. These ties were often sealed only upon the birth of progeny within the arranged marriage. Thus marriage was seen as a union of lines of nobility, not of a contract between individuals as it is seen today.

Royal intermarriage was often practised among European royal families, usually for interests of state. Over time, due to the relatively limited number of potential consorts, the gene pool of many ruling families grew progressively smaller, until all European royalty was related. This also resulted in many being descended from a certain person through many lines of descent, such as the numerous European royalty and nobility descended from the British Queen Victoria or King Christian IX of Denmark.37 The House of Habsburg was infamous for its inbreeding, with the Habsburg lip cited as an ill-effect, although no genetic evidence has proved the allegation. The closely related houses of Habsburg, Bourbon, House of Braganza and Wittelsbach also engaged in first-cousin unions frequently and in double-cousin and uncle-niece marriages occasionally. Examples of incestuous marriages and the impact of inbreeding on royal families include:

  • In ancient Egypt, royal women carried the bloodlines and so it was advantageous for a pharaoh to marry his sister or half-sister;38 in such cases a special combination between endogamy and polygamy is found. Normally the old ruler's eldest son and daughter (who could be either siblings or half-siblings) became the new rulers. All rulers of the Ptolemaic dynasty from Ptolemy II were married to their brothers and sisters, so as to keep the Ptolemaic blood "pure" and to strengthen the line of succession. Cleopatra VII (also called Cleopatra VI) and Ptolemy XIII, who married and became co-rulers of ancient Egypt following their father's death, are the most widely known example.39
  • Among European monarchies Jean V of Armagnac formed a rare brother-sister relationship. Also other royal houses, such as the Wittelsbachs had marriages among aunts, uncles, nieces and nephews.
  • One of the most famous examples of a genetic trait aggravated by royal family intermarriage was the House of Habsburg, which inmarried particularly often and is known for the mandibular prognathism of the Habsburger (Unter) Lippe (otherwise known as the 'Habsburg jaw', 'Habsburg lip' or 'Austrian lip'"). This was typical for many Habsburg relatives over a period of six centuries.40 The condition progressed through the generations to the point that the last of the Spanish Habsburgs, Charles II of Spain, could not properly chew his food.41
  • Besides the jaw deformity, Charles II also had a huge number of other genetic physical, intellectual, sexual, and emotional problems. It is speculated that the simultaneous occurrence in Charles II of two different genetic disorders: combined pituitary hormone deficiency and distal renal tubular acidosis could explain most of the complex clinical profile of this king, including his impotence/infertility which in the last instance led to the extinction of the dynasty.42
  • Francis II from the house of Habsburg-Lorraine married his double cousin Maria Theresa of Naples and Sicily, and several of their children had potentially genetic health problems. Their daughter Marie Anne is said to have suffered from a hideous facial deformity and also being mentally deficient. Their son Ferdinand who became an emperor was also mentally deficient and suffered from Hydrocephalus (meaning water head) which resulted in an enlarged head. He also had several seizures daily. Of course he never was capable of leading the empire and relied on others and abdicated during the difficulties of the Revolutions of 1848. When informed of the revolution he supposedly asked “But are they allowed to do that?” (Viennese German: Ja, dürfen's denn des?) Also five of the children of Francis II died in infancy or early childhood.
  • Another famous genetic disease that circulated among European royalty was hemophilia. This spread to the royal families of Russia and Spain, and was a factor in the overthrow of both. Because the progenitor, Queen Victoria, was in a first cousin marriage, it is often believed that the cause was consanguinity (inbreeding). However, this disease (in males) is generally not aggravated by cousin marriages, although rare cases of hemophilia in girls can occur from the union of hemophiliac men and their cousins.4344
  • Some Peruvian Sapa Incas married their sisters; in such cases a special combination between endogamy and polygamy is found. Normally the son of the old ruler and the ruler's oldest (half-)sister became the new ruler. The Inca had an unwritten rule that the new ruler must be a son of the Inca and his wife and sister.
  • The Chakri Dynasty of Thailand has included marriages between cousins as well as more close relatives. The current king, Bhumibol Adulyadej is a first-cousin once removed of his wife, Sirikit, the two being respectively a grandson and a great-granddaughter of Chulalongkorn. The parents of the king's father, Mahidol Adulyadej, were half-siblings, both being children of Mongkut by different mothers.
  • In the British royal family, marriages to other royals or the nobility and marriages between close relatives, even to first-cousins, was the norm until the generation of the children of the present monarch, Elizabeth II. Elizabeth and her husband Prince Philip, Duke of Edinburgh are third cousins as a result of both being directly descended from Queen Victoria; as well as second cousins once removed as a result of being directly descended from Christian IX of Denmark.45 Queen Victoria herself had married her first cousin, Prince Albert of Saxe-Coburg and Gotha. Their nine children were married into royal and noble families across the continent, tying them together and earning her the nickname "the grandmother of Europe".

Today, royal intermarriage within European royal families has declined compared to past practice along with the power and prevalence of noble families and their importance in international affairs.

See also

References

  1. ^ Inbreeding at Encyclopædia Britannica
  2. ^ Nabulsi MM, Tamim H, Sabbagh M, Obeid MY, Yunis KA, Bitar FF (2003). "Parental consanguinity and congenital heart malformations in a developing country". American journal of medical genetics. Part A 116A (4): 342–7. doi:10.1002/ajmg.a.10020. PMID 12522788. 
  3. ^ Jiménez JA, Hughes KA, Alaks G, Graham L, Lacy RC (1994). "An experimental study of inbreeding depression in a natural habitat". Science 266 (5183): 271–3. doi:10.1126/science.7939661. PMID 7939661. 
  4. ^ Chen X. (1993). "Comparison of inbreeding and outbreeding in hermaphroditic Arianta arbustorum (L.) (land snail)". Heredity 71 (5): 456. doi:10.1038/hdy.1993.163. 
  5. ^ a b Bernstein H, Byerly HC, Hopf FA, Michod RE (1985). "Genetic damage, mutation, and the evolution of sex". Science 229 (4719): 1277–81. doi:10.1126/science.3898363. PMID 3898363. 
  6. ^ a b Michod RE. Eros and Evolution: A Natural Philosophy of Sex. (1994) Perseus Books, ISBN 020140754X
  7. ^ Livingstone, F. B. (1969). "Genetics, Ecology, and the Origins of Incest and Exogamy". Current Anthropology 10: 45–62. doi:10.1086/201009. 
  8. ^ Thornhill, Nancy Wilmsen (1993). The Natural History of Inbreeding and Outbreeding: Theoretical and Empirical Perspectives. Chicago: University of Chicago Press. ISBN 0-226-79854-2. 
  9. ^ Lieberman, D.; Tooby, J.; Cosmides, L. (2003). "Does morality have a biological basis? An empirical test of the factors governing moral sentiments relating to incest". Proceedings of the Royal Society B: Biological Sciences 270 (1517): 819. doi:10.1098/rspb.2002.2290. 
  10. ^ Hartl, D.L., Jones, E.W. (2000) Genetics: Analysis of Genes and Genomes. Fifth Edition. Jones and Bartlett Publishers Inc., pp. 105–106. ISBN 0763715115.
  11. ^ Kingston H M (2002). ABC of Clinical Genetics (3rd ed.). London: BMJ Books. p. 7. ISBN 0-7279-1627-0. PMC 1836181. 
  12. ^ Wolf, Arthur P. and Durham, William H., ed. (2005). Inbreeding, incest, and the incest taboo: the state of knowledge at the turn. Stanford University Press. p. 3. ISBN 0804751412. 
  13. ^ Griffiths, Anthony J. F.; Jeffrey H. Miller, David T. Suzuki, Richard C. Lewontin, William M. Gelbart (1999). An introduction to genetic analysis. New York: W. H. Freeman. pp. 726–727. ISBN 0-7167-3771-X. 
  14. ^ Bittles AH, Grant JC, Shami SA (1993). "Consanguinity as a determinant of reproductive behaviour and mortality in Pakistan". International journal of epidemiology 22 (3): 463–7. doi:10.1093/ije/22.3.463. PMID 8359962. 
  15. ^ Kirkpatrick M, Jarne P (2000). "The Effects of a Bottleneck on Inbreeding Depression and the Genetic Load". The American naturalist 155 (2): 154–167. doi:10.1086/303312. PMID 10686158. 
  16. ^ Leck, Charles F. (1980). "Establishment of New Population Centers with Changes in Migration Patterns". Journal of Field Ornithology 51 (2): 168–173. JSTOR 4512538. 
  17. ^ "ADVS 3910 Wild Horses Behavior", College of Agriculture, Utah State University.
  18. ^ Wolf, Arthur P. and Durham, William H., ed. (2005). Inbreeding, incest, and the incest taboo: the state of knowledge at the turn. Stanford University Press. p. 6. ISBN 0804751412. 
  19. ^ Menotti-Raymond, M; O'Brien, SJ (1993). "Dating the genetic bottleneck of the African cheetah". Proceedings of the National Academy of Sciences of the United States of America 90 (8): 3172–6. doi:10.1073/pnas.90.8.3172. PMC 46261. PMID 8475057. 
  20. ^ Heeney, J.L.; Evermann, JF; McKeirnan, AJ; Marker-Kraus, L; Roelke, ME; Bush, M; Wildt, DE; Meltzer, DG et al. (1990). "Prevalence and implications of feline coronavirus infections of captive and free-ranging cheetahs (Acinonyx jubatus)". Journal of Virology 64 (5): 1964–72. PMC 249350. PMID 2157864. 
  21. ^ Freilich, S.; Hoelzel, A.R. and Choudhury, S.R. Genetic diversity and population genetic structure in the South American sea lion (Otaria flavescens), Department of Anthropology and School of Biological & Biomedical Sciences, University of Durham,U.K.
  22. ^ a b Gilbert, DA; Packer, C; Pusey, AE; Stephens, JC; O'Brien, SJ (1991). "Analytical DNA fingerprinting in lions: Parentage, genetic diversity, and kinship". The Journal of heredity 82 (5): 378–86. PMID 1940281. 
  23. ^ Ramel, C. (1998). "Biodiversity and intraspecific genetic variation". Pure and Applied Chemistry 70 (11): 2079. doi:10.1351/pac199870112079. 
  24. ^ Wright, S. 1922. Coefficients of inbreeding and relationship. Amer. Natur. 56:330-338
  25. ^ Malecot, G. 1048. Les Mathématiques de l'hérédité. Masson et Cie, Paris.
  26. ^ How to compute and inbreeding coefficient (the path method), Braque du Bourbonnais.
  27. ^ Knud Christensen, 4.5 Calculation of inbreeding and relationship, the tabular method, in 14. Genetic calculation applets and other programs.
  28. ^ a b c Tave, Douglas and (1999). Inbreeding and brood stock management. Food and Agriculture Organization of the United Nations. p. 50. ISBN 978-92-5-104340-0. 
  29. ^ G2036 Culling the Commercial Cow Herd: BIF Fact Sheet, MU Extension. Extension.missouri.edu. Retrieved on 2013-03-05.
  30. ^ "Genetic Evaluation Results". Archived from the original on August 27, 2001. 
  31. ^ S1008: Genetic Selection and Crossbreeding to Enhance Reproduction and Survival of Dairy Cattle (S-284). Nimss.umd.edu. Retrieved on 2013-03-05.
  32. ^ Vogt, Dale; Swartz, Helen A.; Massey, John (October 1993). "Inbreeding: Its Meaning, Uses and Effects on Farm Animals". MU Extension. University of Missouri. Retrieved April 30, 2011. 
  33. ^ Top Cat Breeds for 2004. Petplace.com. Retrieved on 2013-03-05.
  34. ^ Preserving Quality and Genetic Diversity in a Dog Breed. bulldoginformation.com
  35. ^ Iceland's 'Kissing Cousins' Breed More Kids. Abcnews.go.com (2008-02-08). Retrieved on 2013-03-05.
  36. ^ Helgason, A.; Palsson, S.; Guthbjartsson, D. F.; Kristjansson, t.; Stefansson, K. (2008). "An Association Between the Kinship and Fertility of Human Couples". Science 319 (5864): 813–6. doi:10.1126/science.1150232. PMID 18258915. 
  37. ^ Beeche, Arturo (2009). The Gotha: Still a Continental Royal Family, Vol. 1. Richmond, US: Kensington House Books. pp. 1–13. ISBN 9-7809-7719-6173. 
  38. ^ Seawright, Caroline. "Women in Ancient Egypt, Women and Law". thekeep.org. 
  39. ^ Bevan, E.R. "The House of Ptolomey". uchicago.edu. 
  40. ^ "The Habsburg Lip", Topics in the History of Genetics and Molecular Biology, Fall 2000. Msu.edu. Retrieved on 2013-03-05.
  41. ^ "The Imperial House of Habsburg: Chapter 5. Web page accessed September 23, 2007". Archived from the original on August 27, 2007. 
  42. ^ Alvarez, Gonzalo; Ceballos, Francisco C.; Quinteiro, Celsa (2009). "The Role of Inbreeding in the Extinction of a European Royal Dynasty". PLoS ONE 4 (4): e5174. doi:10.1371/journal.pone.0005174. PMID 19367331. 
  43. ^ Lock, Stephen; Last, John M. and Dunea, George (2001). The Oxford illustrated companion to medicine. Oxford University Press US. p. 329. ISBN 978-0-19-262950-0. 
  44. ^ Bainbridge, David (2004). The X in Sex: How the X Chromosome Controls Our Lives. Harvard University Press. p. 88. ISBN 978-0-674-01621-7. 
  45. ^ Lewis, Jone Johnson. How are Queen Elizabeth II and Prince Philip related?. Womenshistory.about.com . Retrieved on 2013-03-05.

External links








Creative Commons License