13 Human Population Genetics : its relationship and differences with other branches of human genetics

Dr. Vani Kandpal

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Introduction

 

The fact that human have heritable differences has been acknowledged since ancient times. Early Greek Physicians and Philosophers has not only confirmed this fact but also proposed concepts similar to eugenics. History of Human genetics goes back when Mendel’experiments and Galton’s theory of biometric was proposed. In 1865 Galton came out with the statement in his paper that features of human are transmissible because resemblances between parents and offspring were apparent. Later on Galton with Pearson introduced statistical methods in genetics leading to emergence of biometric genetics. The other leading line of thought was put forwarded by Mendel in 1865 presented in National Science Association in Czech. His laws of inheritance got unnoticed for 35 years and were recognized in 1900 by Correns, Tshermak and De Vries. Mendel’s insights lead to development of human genetics. Human genetics deals with inheritance among human as it occurs. The branches of human genetics are many and its borders are indistinct. Many of them overlap and are not mutually exclusive. Human molecular genetics deals with identification and analysis of genes at DNA levels. Polymerase chain reaction (PCR), blotting methods and gel electrophoresis are being used in this branch. Human biochemical genetics deals with biochemistry of nucleic acids, enzymes and proteins in normal and mutant individuals. This branch mainly uses chromatography and enzymatic assays. Human cytogenetics deals with study of human chromosomes with respect to health and disease. Immunogenetics deals with genetics of blood groups, tissue antigens such as HLA types and other components of immune system. Formal genetics deals with segregation and linkage studies. Clinical genetics deals with diagnosis, prognosis and to some extent treatment of genetic diseases. Genetic screening and counseling is an important domain of this branch of human genetics. Behavioural genetics attempts to understand the hereditary factors underlying behaviour in health and disease. They unravel the genetic factors responsible for our personality and cognitive skills. Genetics of mental retardation and psychiatric disease are also considered in this domain. Developmental genetics deals with genes controlling growth and development of organisms. Reproductive genetics focuses on reproductive and fertility issues which affect families such as genetic and chromosomal abnormalities.

 

Human Population Genetics

 

Human population genetics is one of the important disciplines interwoven with many allied subjects. It deals with the behaviour of genes in large groups and it concerns with a number of micro evolutionary forces like genetic drift, migration, mutation and selection in human populations. The structure and gene pool of human populations are studied by considering gene frequencies of whole lot of genetic markers. Human population genetics deals with distribution and changes in gene and genotype frequency in a population and predicting the way it would change overtime under the influences of various factors.. While the genotype frequencies are easily measured, their change is not. Changes in the allele frequencies are impossible to observe directly. Though one can observe the state of population, there is really no way to explore directly the evolution of a population. Thus, most important insights of human population genetics came initially from theory. Population geneticist focus on two main things: describing genetic structure of population and theorizing on evolutionary forces acting on the population. A description of genetic structure of a population is seldom simply a list of genotypes, but rather relative frequency of alleles and genotypes. The foundation stone of the theoretical population genetics was discovery of a simple relationship between allele frequency and genotype at an autosomal locus in an equilibrium randomly mating population. This relationship was named as Hardy Weinberg equilibrium, which describes state of single locus in a randomly mating population, free of evolutionary forces such as mutation, migration, natural selection and genetic drift. The frequency of alleles does not change as a result of random mating. Random mating can change genotype frequencies, not allele frequencies. Though Hardy Weinberg equilibrium was applicable on population of infinite size. However, population size of many species is not large. In finite sized populations random changes in allele frequencies affect evolution. Genetic drift was the name given to the consequence of these random changes. This concept of non-directional change in allele frequency is also known as Sewall Wright Effect owing to his contribution to fundamental topics of population genetics. The result of natural selection, one of the evolutionary force, is evident but difficult to observe the time of course of change. Natural selection works when different genotypes have different fitnesses. Thus, increasing the genotypes which have better adapted with changing environment. In addition to these factors, inbreeding, a form of non random mating, also leads to deviation from hardy Weinberg equilibrium. Inbreeding occurs when individuals are more likely to mate with relatives than with randomly chosen individuals. This leads to increase in the frequency of homozygotes which has a detrimental effect. Inbreeding depression is the phenomenon of lower fitness with higher levels of inbreeding. In last few years population geneticis t have become interested in the epidemiology of complex genetic disorders that require biometric techniques.

 

Human Population Genetics and Human Molecular Genetics :

 

Molecular genetics studies genes at molecular level. It employs method of molecular bio logy to understand this branch. The polymerase chain reaction used to amplify the required region for study has been a breakthrough for the other branches of human genetics. The Human genome project (HGP) which began in 1990s was a molecular genetics project. It was aimed at generating the sequence of 3 billion base pairs that is the whole genome. It was expected that it will lead to better understanding of the genetic diseases. After completion of HGP, genetic variabilities among individuals began to attract researcher’s focus. There are approximately 10 million single nucleotide polymorphisms (SNPs) in human genome. A worldwide effort known as the HapMap Project is mapping SNPs and other genetic variants in human populations around the world. By mapping the distribution of SNPs among different human populations, researchers can begin to learn which types of variation are most common in certain regions of the world. The project has identified over 3.1 million SNPs across the human genome that is common among individuals of African, Asian, and European ancestry. The genetic diversity between different populations came to light as a result of these projects. In addition to this, the project led to unravelling population specific variants responsible for certain disease confined to the respective areas. The genetic epidemiology has become an evolving field owing to wealth of data, generated through human genome project and hapmap project. Next generation sequencing technique, which is development in the field of molecular genetics, is making a substantial impact on genetic diversity in populations.

 

Human Population Genetics and Behavioural genetics :

 

Human behavioural genetics deals with the effect of genetic and environment on the behaviour. It’s a highly interdisciplinary subject involving psychiatry, genetics, biology, epigenetics and statistics. The study designs for the subject include family studies, twin studies and adoption studies. These methods are used as they disentangle the environmental and genetic component. Thus, elucidating the extent to which genetics contributes towards the behavioural trait. This discipline studies both mental and psychiatrc disorders like schizophrenia, bipolar disorder, alcoholism etc. Earlier the study on behavioural genetics was confined to hospital based case control studies. But now the mental health has become an important aspect of population genetics. Lately it has been reported that certain populations are more prone to have specific mental disorders. For instance, tribal/ primitive societies which were found to be having rare incidence of self destructive tendencies, have been reported to have higher inclination towards suicides. Individuals of Polar peoples, North and South American Indians, Bedouins, Melanesians, Micronesians, Polynesians, peoples of the Caucasus and native races of British India were found to have high rate of suicides as compared to civilized populations (Steinmetz (1984)). Recently a study on Idu mishmi tribe of Arunachal Pradesh revealed strong prevalence of suicidal behaviours ( Mene 2014). Schizophrenia is a mental disorder, characterised by profound disruptions in thinking, affecting language, perception, and the sense of self. It appears to be most common in Japan, Oceania, and Southeastern Europe and least common in Africa (Ayuso 2013a). Obsessive-compulsive disorder is two to three times as common in Latin America, Africa, and Europe as in Asia and Oceania (Ayuso 2013b). The distribution of these disorders to be high in specific populations suggest the genome of populations to be increasing susceptibility towards them. Examining the genes, associated with mental disorders in a population, in the light of concept of population genetics, might lead to the risk get transmitted to next generation.

 

Human Population Genetics and Immunogenetics :

 

Immunogenetics deals with the genes involved in immunity. This field began with the discover y of Louis Pasteur, Roert Koch, who worked on controlling of infectious diseases. The immune system recognizes substances as either native to one’s own body or foreign ( non-self). Antigens are the substances that provoke immune system. They are protein mo lecules embedded in surface of bacteria, viruses. Other antigens are part of glycoprotein, lipoproteins or nucleoproteins. Thus any difference in the sequence in genes encoding these substances may lead to different antigens. These distinctions contribute towards, large number of blood types and tissue types. Red blood cells make up 455 of the blood volume. Mature red blood cells have no nuclei but is packed with haemoglobin. Hemoglobin carries oxygen to other parts of the body. On the surface of the red blood cells, there are many types of proteins, receptors, enzymes, transport system and cell recognition molecules. These cell surface molecules, act as an antigens foreign to other species. One such set of antigens determines the ABO blood group. The presence of any antigen is revealed by a chemical reaction with corresponding antibody. Agglutination is the process which occurs when an antigen and its antibody react. They form clumps, which are rarely needed to see with the help of microscope. The blood group are defined as A, B , AB and O on the basis of presence of antigen A, antigen B, alleles A and B both; and no antigen at all , respectively. The development of this field not only helped blood transfusion, but also was useful for population genetics. The frequency of blood groups varies across the world because of the selection of certain blood groups against the diseases confined to the respective areas. The molecular basis of blood group system was elucidated in 1990 (Jenkins and Odonell 2006). The ge ne encodes a gylcosyltransferase, which transfers N- acetyl D- galactosamine (group A) or D- galactos (group B) to the non reducing ends of glycans on glycoproteins and glycolipids. The group O phenotype results from inactivation of the A1 glycosyltransferase gene, and non reducing ends of corresponding glycans in group O subjects express the blood group H antigen. ABH antigens are widely expressed in body fluids and tissues. One of the significant disease associations described for non) versus O group was their susceptibility towards arterial and venoum thromboembolism (VTE). Non group O patients have greater risk of VTE . These observation raised possibility that greater propensity for clot formation was present in non-O patients. This conferred a survival advantage to non O patients. Recently evidence supporting group O providing selective advantage against malaria have been found. Group O is presumed to have emerged in Africa before the migration of early humans. Severe malaria results in the death of million each year before they reach reproductive age and therefore selects survival. (Anstee 2010). Rowe et al., reported reduced resetting of Plasmodium falciparum isolates from group O Malian children compared to non –O blood groups. Parasitized red cells form rosettes with uninfected red cells and adhere to vascular endothelium, causing vaso occulusion and severe diseases. Infectious diseases can also be directly linked to ABO phenotype. Numerous studies have shown that once a person is infected with cholera the person with phenotype O confers greater likelihood of severe infections than non O blood group phenotypes. This suggested low prevalence of group O and high prevalence of group in the Ganges delta of Bangladesh is directly related to selective press ure from cholera (Glass 1985). Another proven association of blood group polymorphism with disease was that between group O and peptic ulcers. The gastric pathogen H pylori is known to be causative agent leading to peptic ulceration and gastric cancer. Studies demonstrated that the strain of H pylori was bound to blood group O Leb but not A Leb structures on the gastric epithelium. Thus providing a clear explanation for greater susceptibility of group O secretors. Extensive studies are being carried on, in the context of blood group association with diseases. Work in the field of Immunogenetics, further furnished the knowledge regarding ABH antigen, leading to the reporting of global frequency distribution of ABO antigens. These observational studies brought to light the selective pressures which ABO antigens were experiencing owing to their chemical or structural nature.

 

Human Population Genetics and Biochemical genetics : Biochemical genetics deals with normal and mutation forms of genes associated with enzymes, nucleic acids and proteins. This branch involves study of many heritable diseases including sickle cell, thalassemia, G6PD deficiency and other inborn errors of metabolism. Sickle cell anemia is an autosomal recessive disease associated with abnormality in haemoglobin. There are three types of haemoglobin A, A2 and F. Hb A constitutes the major part in normal adults. It consists of two alpha chains of 141 amino acids and two beta chains of 146 amino acids. It was found that a hereditary anemia, prevalent among Black Americans, was caused by abnormal haemoglobin which has lower electrophoretic mobility than Hb A. Ingram showed that this abnormal Hb S, differed from Hb A by a single amino acid substitution. The amino acid glutamic at 6 position, o f 146 beta chain of Hb A, was replaced by valine in Hb S. The sickle cell polymorphism is mostly limited to people of African origin. These areas have high incidences of malaria, especially caused by Plasmodium falciparum. The high frequency of HbS in these areas is attributed to heterozygote AS being at advantage. The homozygote SS has severe anemia and survival is low, while Hb AA are susceptible towards malaria. The heterozygote AS have an increased resistance towards malaria as the malaria causing microorganism is not able to thrive in sickle cells. Studying the underlying polymorphism of HbS, helped in understanding the distribution of HB S frequency distribution. Thus, this aspect of biochemical genetics explained Hb S being an example of balanced polymorphism. Similar is the case of G6PD deficiency. This deficiency is an X –linked recessive inborn error of sugar metabolism which occurs due to deficiency of glucose-6-phosphate dehydrogenase (G6PD). G6PD deficiency mainly occurs in population that live in those Mediterranean regions in which malaria is prevalent and is probably associated with an increased resistance to malarial infection. Though no direct estimates of genotype fitness are there, yet high frequencies for the gene of G6PD deficiency are known in some jewish populations, which must have originated from population with very low frequencies for this gene in a comparatively short time. This suggests selection associated with G6PD deficiency. Since Palestine is not an area with high incidence of malaria, it seems likely that G6PD among original migrants were low. The high frequency now found in some areas would then have to be explained by subsequent selection, suggesting that selection coefficients were strong enough to change the frequency. The wide variation in frequency data on G6PD deficiency reflects the G6PD alleles being transient polymorphisms. The intensity of selection due to malaria and time available may vary from place to place, which has led to different frequencies. Thus, another study of the field of biochemical genetics led to understanding of the frequency distribution of G6PD deficiency allele. These two branches are overlapping fields, where observation of one field unravels mysteries of the other field.

 

Human Population Genetics and Clinical genetics:

 

In some of the populations, non random mating takes place. Inbreeding is one type of such matings. Inbreeding refers to mating between closely related individuals. It results in increased homozygosity which comes about because of shared ancestry. Rare recessive genotypes become much more common in inbreeding. This increased proportion of homzygotes influences the fitness of the population due to expression of rare recessive genetic disorders. Here comes the role of gene tic screening and counselling in such populations where inbreeding is practised. Genetic screening is the search of population for the persons having a particular genotype or karyotype that can cause serious disease. Screening serves two purposes. First it detects predisposition before the onset and second it identifies the unaffected carriers and counsel them about the risk of producing affected children. The aim of genetic counselling is to convey medical and genetics facts to an affected or potentially a ffected family in a way that can be understood. Genetic counselling requires professionals who are thoroughly grounded in genetics and medicine. Amish population in US have been found to have development delays. For decades, the Amish have been the focus of research on genetic disorders, in part because they have a small gene pool and due to high rates og inbreeding certain genetic diseases appear more often than in genetically diverse populations. Recently mutation responsible for the delays in this pop ulation has been identified. A genetic study conducted, on 15 individuals of the Old Order Amish Community in Ohio, found a mutation in the HERC2 gene. This is the first time this gene has been associated with human disease. Hemophilia is another such disease which runs in the royal families of Europe. Genetic screening in such population might examine the prevalence or the risk of producing affected offspring’s. After screening, genetic counseling of the individuals carrying the mutation might lower the incidence of developmental delays in them.

 

Summary:

 

  • Human population genetics is one of the important disciplines interwoven with many allied subjects.
  • It deals with the behaviour of genes in large groups and it concerns with the evolutionary forces lik e genetic drift, migration, mutation and selection in human populations.
  • Population geneticist focus on two main things: describing genetic structure of population and theorizing on evolutionary forces acting on the population.
  • The foundation stone of the theoretical population genetics was discovery of a simple relationship between allele frequency and genotype at an autosomal locus in an equilibrium randomly mating population.
  • Hardy Weinberg equilibrium, which describes state of single locus in a randomly mating population, occurs in population free of evolutionary forces such as mutation, migration, natural selection and genetic drift.
  • Molecular genetics studies genes at molecular level. It employs method of molecular biology to understand this branch. Human genome project (HGP), which began in 1990s was a molecular genetics project, reported approximately 10 million single nucleotide polymorphisms (SNPs) in human genome. By mapping the distribution of SNPs among different human populations, variation among individuals of African, Asian, and European ancestry was examined. The project led to unravelling population specific variants responsible for certain disease confined to the respective areas.
  • Human behavioural genetics deals with the effect of genetic and environment on the behaviour. The study designs   for  the  subject  include  family studies,  twin studies  and adoption studies.  These methods are used as they disentangle the environmental and genetic component. But now the mental health has become an important aspect of population genetics. Lately it has been reported that certain populations are more prone to have specific mental disorders. Examining the genes, associated with mental disorders in a population, in the light of concept of population genetic s, might lead to the risk getting transmitted to next generation.
  • Immunogenetics deals  with the  genes  involved  in  immunity.  Antigens  are  the  substances  that provoke immune system. On the surface of the red blood cells, there are many types of proteins, receptors, enzymes, and transport system and cell recognition molecules. These cell surface molecules, act as an antigens foreign to other species. One such set of antigens determines the ABO blood group. The study of ABH antigen not only helped blood transfus ion, but also was useful for population genetics. The frequency of blood groups varies across the world because of the selection of certain blood groups against the diseases confined to the respective areas. Work in the field of Immunogenetics, further furnished the knowledge regarding ABH antigen, leading to the reporting of global frequency distribution of ABO antigens. These observational studies brought to light the selective pressures which ABO antigens were experiencing owing to their chemical or structural nature.
  • Biochemical genetics deals with normal and mutation forms of genes associated with enzymes, nucleic acids and proteins. This branch involves study of many heritable diseases including sickle cell, thalassemia, G6PD deficiency and other inborn errors of metabolism. Distribution of sickle cell anaemia, G6PD deficiency and other diseases helped in understanding the selection pressures working on the genes related to these diseases.
  • In some of the populations, non random mating takes place. Inbreeding is one type of such matings. Inbreeding refers to mating between closely related individuals. It results in increased homozygosity which comes about because of shared ancestry. Rare recessive genotypes become much more common in inbreeding. Here comes the role of genetic screening and counselling in such populations where inbreeding is practised. Genetic screening in such population might examine the prevalence or the risk of producing affected offspring’s. After screening, genetic counselling of t he individuals carrying the mutation might lower the incidence of developmental delays in them.

 

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References:

  • Mange, A.P. and E.J. Mange. 1998. Basic Human Genetics, Second Edition. Sinauer Publishing, Sunderland, MA.
  • Cavalli-Sforza, L., 1999. The Genetics of Human Populations, Dover Publications, New York
  • Gilespie JH. 1998. Population genetics: A concise guide. John Hopkins University Press. Baltimore and London.
  • Vogel F   and  Motulsky  AG.   2010  Human  Genetics:  Problems    and  Approaches.   Forth  Edition.Springer-Veralg.
  • Steinmetz, S.R., 1984. Suicide among primitive peoples. American Anthropologist 7 (1), 53–60.
  • Ayuso-Mateos, Jose Luis. “Global burden of schizophrenia in the year 2000” . World Health Organization. Retrieved February 27, 2013.
  • Ayuso-Mateos, Jose Luis. “Global burden of obsessive-compulsive disorder in the year 2000” . World Health Organization. Retrieved February 27, 2013
  • Jenkins PV, O’Donnell JS. ABO blood group determines plasma von Willebrand factor levels: a biologic function after all? Transfusion 2006;46(10):1836-1844.
  • Rowe JA, Handel IG, Thera MA, et al. Blood group O protects against severe Plasmodium falciparum malaria through the mechanism of reduced rosetting. Proc Natl Acad Sci U S A 2007; 104(44):17471-17476.
  • Glass RI, Holmgren J, Haley CE, et al. Predisposition for cholera of individuals with O blood group.
  • Possible evolutionary significance. Am J Epidemiol 1985; 121(6):791-796.
  • Anistee DJ. The relationship between blood groups and disease. Blood. 2010 Jun 10; 115(23)