Chapter XIII -Medical Biology - course content Genetics 2023-2024.pdf

Exercise 13. Topic: Population genetics – selected issues. Glossary: Gene pool of the population - the sum of all alleles present in a given population at a given time. Genetic distance - the assessment of the differences in the frequencies of alleles; is based on similarity/differences between gene...

Exercise 13. Topic: Population genetics – selected issues. Glossary: Gene pool of the population - the sum of all alleles present in a given population at a given time. Genetic distance - the assessment of the differences in the frequencies of alleles; is based on similarity/differences between genetic sequences e.g. microsatellite in different species; it allows to evaluate evolutionary relationships between populations (determine kinship of individuals, varieties, species, etc.)and also to determine the time of evolutionary lines divergence. Genetic distance is the degree of genetic difference (genomic difference) between species or populations,which is measured by some numerical methods. Genetic drift– the random fluctuation frequency of the alleles in the population. Random change in the frequency of alleles in subsequent generations, especially visible in small populations. Genetic diversity of the population – the diversity within the population, most often determined by the level of its heterozygosity, differentiation of gene alleles in gene pools of the population of a given species. Genetic variability of the population – the resultant rate of mutation, genetic drift, features /demographic processes of population (population structure, migrations) and in the case of functional changes - selection, conditioning genetic diversity. Haplotype – the combination of alleles on each chromosome. The group of alleles of different genes on a single chromosome that are closely enough linked to be inherited usually as a unit (as of the major histocompatibility complex). Heterozygosity (H) – the proportion of heterozygotes in the population (percent of heterozygotes to homozygotes); the probability that a given individual will be heterozygous at a particular locus; indicates the genetic diversity of the population. Different alleles are present at one or more loci on homologous chromosomes. Mendelian population = panmictic population -a set of individuals of the same species in a given area, having a common gene pool in which panmixia occurs, i.e. random crossing of individuals (mating of individuals from each part of a given population with equal probability).Each individual can cross with any individual of the opposite sex belonging to this population with equal probability, which ensures free flow of genes in the population. Population – a communityof individuals of the same species, who live in a particular geographic area at the same time, with the capability of interbreeding. Selection - the process of elimination of genotypes/phenotypes unfavourable in given environmental conditions (negative selection); if environmental factors work in favour of certain genotypes/phenotypes - positive selection. Variance– a numeric indicator that determines the degree of data dispersion around the average,is the sum of the squares of deviations of individual values ( reduced by one:. ) from their mean ( ) divided by the number of cases observed (n), Population genetics Population genetics analyzes the phenomena of heredity in relation to the population (exactly the gene pool of populations) of sexually reproducing organisms. The basis of the population genetics is the Hardy-Weinberg principle, which defines the frequency of alleles and the frequency of genotypes in the population and changes in their occurrence under the influence of evolutionary factors. It was formed in 1908 independently by English mathematician Godfrey Hardy and German physician Wilhelm Weinberg. Hardy-Weinberg principlesays that in a population, i.e. in a state of genetic equilibrium (a balanced stationary population) the prevalence of genotypes depends entirely on the frequency of alleles and is constant from generation to generation. The panmictic population (Mendelian) is characterized by:  very large (in theory - infinite) population size,  randominterbreeding of all individuals with each other (diploid individuals, sexually reproducing)in the population (panmixia)- individuals have equal chances of having offspring (lack of selectivity in reproductive relationships); genetic equilibrium with random association is achieved in one generation;  lack of factors disrupting genetic balance (causing changes in the frequency of alleles in the gene pool): migration (gene flow), mutation, selection, genetic drift. In natural populations, we observe the occurrence of many demographic processes and the operation of the above-mentioned factors causing quantitative changes disrupting the genetic equilibrium (the so-called. primary genetic equilibrium)- being the cause of evolutionary changes. The Mendelian population model allows to understand the process of evolution of organisms, genes and genomes, assessment of biodiversity, as well as running breeding programs for endangered species and reconstruction of kinships between organisms at all taxonomic levels. The population is in a genetic equilibrium if the condition is met: p + q = 1 i p2 + 2pq + q2 = 1 where: the frequency of the dominant allele means p, the frequency of the recessive allele means q, the frequency of genotypes: dominant homozygotes - p2, recessive homozygotes - q2, heterozygotes - 2pq. How to determine the equilibrium for the population? It is necessary to compare the frequency of alleles and genotypes in the studied population resulting from the observed real frequency of phenotypes with the frequency of alleles and genotypes calculated from the Hardy-Weinberg principle: if the total number of individuals in the population is N, the total number of alleles of a given gene in the population = 2N, the number of homozygous individuals: dominant AA=D, recessive aa=R, heterozygous individuals Aa=H, then D + H + R = N, the number of dominant alleles P is 2D+H, the number of recessive alleles Q is 2R+H; Example: In a population of 250 individuals, we have 25 AA, 145 Aa, 80 aa (Σ=250), the total number of alleles is 500,hence, we calculate the frequencies of individual genotypes: D=f(AA)=25/250=0.1, H=f(Aa)=145/250=0.58, R=f(aa)=80/250=0.32, number of dominant alleles: P=2x25+145=195, recessive alleles: Q=2x80+145=305, and allele frequencies are: f(A)=195/500=0.39; f(a)=305/500=0.61. At the state of genetic equilibrium, the frequency of dominant homozygotes should be 0.392=0.15, heterozygotes 2x0.39x0.61=0.48, recessive homozygotes 0.612=0.37,which is inconsistent with the data observed in the population.The population being studied is not in a state of genetic equilibrium. Hardy-Weinberg's principle can be used:  for traits linked with the X chromosome (for X-linked inheritance) - it takes the form for a male population: p+q=1 [the frequency of men showing the dominant trait P(XHY)=p, and the frequency ofmen showing a recessive traitP(XhY)=q]; for the female population: p2+2pq+q2=1 [P(XHXH)=p2, P(XHXh)=2pq, P(XhXh)=q2];  for multiple alleles and traits inherited in this way – e.g. for 3 pairs of alleles, it has the form: p+q+r=1, (p+q+r)2=1, p2+2pq+2pr+2qr+q2+r2=1. Factors disturbing the genetic equilibrium of the population Mutations They are the cause of the formation of new alleles; they change the frequency of genes, may affect the phenotype and disrupt important vital functions of the body, lowering vitality, fertility and even causing death.The result of various types of mutations are polymorphisms affecting the genetic diversity of the population. Not all mutations are revealed in a generation, and not all will be passed on to next generations. Changing the adaptive properties of an organism,due to a mutation, can lead to the fixation of this mutation as a result of selection. The value of the mutation (associated with the chance of survival, production of offspring) depends on the environmental conditions and the genetic background e.g. heterozygotes with sickle-cell trait HbAHbS in areas of malaria. The genome of modern species is a record of the changes that have occurred in the course of evolution. Selection The phenomenon of elimination (negative selection) or preference (positive selection) of certain individuals (the same certain alleles and/or genotypes) of the population, prevents leaving offspring (transferring their genes to the next generation), or favouring certain individuals. It leads to a reduction in the genetic diversity of the population. It can work at the level of gametes, l individuals or entire populations. The driving force of selection isan environmental change as well as intra- and interspecies competition. Example: Positive selection – higher frequency of heterozygotes with sickle-cell trait (sickle cell anaemia) HbAHbS in the endemic areas of tropical malaria caused by Plasmodium falciparum; the privilege of heterozygous compared to homozygous HbAHbA (they are suffering from malaria) and HbSHbS (indicates sickle cell anaemia - severe haemolytic anaemia). Haemoglobin HbS induces expression of heme oxygenase enzyme HO-1, which breaks down heme and causes, among others, the production of Carbon monoxide CO (by-product of the reaction), which in turn inhibits the symptoms of cerebral malaria.Haemoglobin HbS also has an immunomodulatory effect. Migration, gene flow – emigration migration -the movement of individuals from the studied population outside.Each subject takes two alleles of the gene being tested. Immigration - movement of individuals from the outside to the studied population. Each subject brings with him two alleles of the gene being tested. Populations rarely remain completely isolated from each other, at the same time subpopulations occur in them, separated by ethnic and cultural barriers, economic or geographical. In isolated and small populations, the effects of genetic drift are revealed. Genetic drift Genetic drift is a random change in the frequency of alleles in subsequent generations as a result of random fluctuations (irregular fluctuations in the population size).It results from the random transfer of alleles to the offspring and various random events that can eliminate certain individuals from the population. It is particularly visible in small populations in which the probabilities of events show significant deviations from the law of large numbers(Bernoulli's law: "with a probability close to 1, it can be expected that with a sufficiently large number of attempts, the frequency of a given random event will be arbitrarily little different from its probability"). The frequency of occurrence of a gene can significantly diverge in different generations of such a population. It is invisible in large populations. Genetic drift can increase or decrease the frequency of genes causing disease.The drift, however, does not cause significant deviations from the Hardy-Weinberg principles in the case of random mating (association), although it changes the frequency of alleles in the population. Rare genetic diseases can be observed quite often or less frequently in lowpopulation size.Phenylketonuria and cystic fibrosis, common in the Caucasian population, are relatively rare in Finland (the Finnish population was founded by a small group of people about 100 generations ago). The genetic composition of contemporary populations is conditioned by previous generations. A special case of genetic drift is the situation when in the past there was a significant decrease in the population size which occurs due to the founder's effect (e.g. due to the migration of a small number of individuals and the creation of a new population) and the effect of "population bottleneck" (genetic bottleneck, bottleneck non-selective drastic reduction in size of population due to environmental events: natural disaster [earthquakes, floods, fires, disease], or pandemic). This case causes that such a population will have a significantly different and depleted genetic pool in relation to the starting population. With the passage of time it may lead to the accumulation of alleles that cause the occurrence of diseases (South African porphyria with Afrikaners-Dutch settlers who came to Africa in the middle of the 17th century; achromatopsia - colour blindness in the population of the Micronesian island of Pingelap). Examples of autosomal dominant traits in humans (for the analysis of allele frequencies from the Hardy-Weinberg principle) Table 1. Monogenic traits in humans conditioned by genes. Dominant Recessive Dark hair Fair hair Non-red hair Red hair Curly hair Straight hair Gray strand of hair present Lack of gray strand of hair Freckles Lack of freckles Dark eyes Bright eyes Separated eyebrows Joined eyebrows Widow’s peak Lack of widow’s peak Darwin's tubercle (auricular tubercle) Lack of Darwin's tubercle (auricular tubercle) Free earlobe Attached earlobe Protruding (outstanding) ears Normal ears Dimples In the cheek Lack of dimples In the cheek Diastema - a gap between two teeth Lack of diastema Ability to roll tongue U Lack of ability Ability to lift the end of the tongue up Lack of ability Ability to feel the bitter taste of phenylthiourea Lack of ability Cleft chin Smooth chin Aguiline nose (Roman nose) Tendency to use the right hand Straight nose Hand clasping -the right thumb to the left Hand clasping -the left thumb to the right Interlacing fingers – the left thumb to the right Interlacing fingers – the right thumb to the left Tendency to use the left hand Monogenetic disorders Mid-digital hair present Lack of mid-digital hair Blood type A and B Blood type 0 Lack of disorder Alkaptonuria Lack of disorder Phenylketonuria Lack of disorder Albinism Lack of disorder Tyrosinemia Achondroplasia Lack of disorder Marfan syndrome Lack of disorder Huntington's disease Lack of disorder Lack of disorder Cystic fibrosis Familial hypercholesterolemia Lack of disorder Laterality It is the dominance of one side of the brain in controlling particular activities or functions, or of one of a pair of organs such as the eyes or hands. Functional advantage of one side of the body over the other; examples include right/left-handedness and right/left-footedness. Autosomal dominant or multifactorial trait. An important element of the child's motor development is the correct course of lateralization process, which in the majority of children is accomplished between 6 and 10 years of age. With the establishment of the dominance of the right side of the body,the dominance of the left hemisphere of the brain is shaped, in the case of the dominance of the left side of the body – right cerebral hemisphere is dominant. There is a significant variation in the functions of the cerebral hemispheres: the left hemisphere works in an analytical way, e.g. it differentiates letters, notes in them "tails, dashes", arranges information sequentially, i.e. element by element, is responsible for receiving time, receives and recognizes sounds of speech, and also performs complex verbal operations. The right hemisphere, for example, works in a global, holistic way, processes new stimuli, recognizes, it is guided by the physical similarity of the "whole” stimulus, not its elements, processes and stores mathematical and musical information (Table 2). People leftoriented (left hand, eye, ear, leg) and more often using the right cerebral hemisphere are in a much more difficult situation when they have to learn to read, write, spell or mathematics in a characteristic way for the left hemisphere. People who have crossed laterality, i.e. some of the dominant organs are on the right (e.g. hand), and some - on the left (e.g. eye) have difficulty to coordinate the hand and eye. Ambidexterity - it may have a primitive character (it may be of primary nature) - it is more common in primitive people as a secondary trait - the effect of less-privileged hand exercises. Table 2. Asymmetry of brain function - specialization of the cerebral hemispheres. left hemisphere right hemisphere mathematics understanding of the content logical thinking writing reading speech perception of the face imagination understanding of music sculpturing spatiality skill in dancing analysis digits symbols, e.g. notes synthesis image geometric figures musicality simultaneity of perception sequentiality of perception In order to determine the laterality pattern, a leg, hand, eye and ear examination should be performed. Observe the child during everyday activities and presented selected "fun" tasks (e.g. examining the dominant hand - throwing beads, small blocks into a narrow bottle, unscrewing the jars, examining the dominant eye - looking through the hole cut in the carton, examining the dominant leg - kicking the ball, standing on one leg; examining the dominant ear - listening to the playing small radio ). We determine the laterality pattern by stating, which hand and foot the child uses to performtasks and with which eye they look and with which ear they prefer to listen. In the case of a child with a disorder of communication (e.g. a child with autism) the diagnosis should be performed by a specialist to determine the laterality pattern.The side domination test can be carried out from the third year of age. Therapy should include those children who, after the age of three, have: left-sided l laterality, crossed laterality, non-fixed laterality. Greater efficiency of the right or left hand is not a typical human feature - over 30% of chimpanzees are left-handed. The left-handed people are the largest minority in the world. They constitute 10% of humanity. A child who starts school education can have great difficulty in learning, if the process of determining laterality has not been completed. Difficulties may include reading - not only learning to read, but also reading comprehension skills (these skills depend mainly on the left hemisphere of the brain - centres conditioning the ability to sequential recognition of letters, syllables and words, and then putting them into sentences and understanding their meanings). The right hemisphere is responsible for the reception of overall sensations - previously seen linguistic structures. The left cerebral hemisphere is responsible for spelling and grammar; when they "deal with" the right cerebral hemisphere, we make many mistakes, rearrange the letters, and confuse the inflection endings. The ability to feel the tasteof phenylthiocarbamide In the human population, as well as the apes, we can distinguish two classes: those who feel and do not feel the bitter taste of phenylthiocarbamide (PTC) and its chemical relative, 6-n-propylthiouracil (PROP).Phenylthiocarbamide also known as phenylthiourea (PTU), is an organosulphur thiourea containing a phenyl ring,organic chemical compound from the group of aromatic nitrogen compounds C6H5-NH-CS-NH2, a derivative of organosulphur thiourea containing a phenyl ring (chemical group N-C = S is responsible for the characteristic bitter taste). Both PCT/PROP are used as a marker in population-genetic studies in testing the sensation of bitter taste. This is a allelomorphic feature - the allele of T sensitivity is dominant. The frequency of alleles and phenotypes is different in different populations. The distribution of the phenotypic variability of PTC taste sensibility in the human population shows a bimodal distribution - different is the feeling of homozygous (TT), different in heterozygous genotypes (Tt). As a result of occurring SNPs (Single Nucleotide Polymorphism) in the gene TAS2R38in three places,there are 5 haplotypes and different phenotypes of phenylthiocarbamide flavour sensitivity. The feeling of bitter taste is mediated by a group of receptor proteins that are found on the surface of the cells in the taste buds of the tongue. Small differences in the structure of these proteins determine different degrees of sensitivity to bitter taste. There are usually only two forms of the gene in Europeans and Asians, which allows to detect the bitter taste of PTC and substances similar to it, e.g. goitrin, which occurs in cruciferous vegetables such as cabbages, broccoli, brussels sprouts. Goitrin reduces the production of thyroid hormones such as thyroxine. In Africa, the gene for PTC occurs in a larger number of varieties than in other populations. This means that the population of Africa has a greater variability in the sense of bitter taste. Evolutionary biologists explain the benefits of this to distinguish edible from poisonous plants that are often bitter, which in ancient hunter-gatherer communities was crucial for survival. On the other hand, edible plants containing compounds with a bitter taste are usually rich in vitamins. The frequency of people sensitive to PTC in different populations: - Australian Aborigines - 27%, - Europeans – 72-75%, - Chinese - 93%, - North American Indians - 97%. There is a correlation between the sensitivity to PTC and the tendency to some diseases. It has been shown that people who are insensitive to PTC are more likely to suffer from hypothyroidism, and among those who feel the bitter taste of PTC, overactive thyroid gland (hyperthyroidism) is more common. The addiction to smoking is more common among people who are insensitive to PTC, and less often among those who taste PTC. The frequency of people who are insensitive to PTC is particularly high, including people with mental retardation, in whom it results from congenital hypothyroidism. Sensitive to PTC, they rarely suffer from diabetes, nodular goiter of thyroid gland (nodular thyroid goiter), goiter with hypothyroidism. Coalescent theory Population studies using DNA markers have found their application in research on human evolution and migration of human groups. Conducting such studies significantly facilitated the analysis of mitochondrial DNA (mtDNA) and recombined DNA sequences of the Y chromosome and non-recombinant DNA sequences of the Y chromosome or analysis of single nucleotide polymorphisms within the entire human genome. The genetic diversity of native (indigenous) Africans is now much greater than that of highly migrating populations (e.g., American Indians). At each stage of migration, only a subgroup sets out on a journey, taking away only part of the genetic diversity from the initial population. Analysis of the mitochondrial and nuclear DNA obtained from remains of prehuman and prehistoric human forms, and the comparison with the mtDNA of modern man indicate the path of evolution. The use of the coalescence analysis technique (coalescence) allowed to reconstruct and establish connections between sequences and to restore the sequence of appearance of individual mutations in the haplotype of genealogical lines. As far back in time, sequence lines carrying a new allele created as a result of mutations were merging gradually until they came together at one point in the past, in the "closest common ancestor" sequence (MRCA – most recent common ancestor). Elements of population genetics - practical application in medicine Contemporary populations, including human population, exhibit genetic diversity illustrating the process variability resulting fromthe occurrence of mutation action of genetic drift and selection. Demographic and historical processes are also factors influencing the shaping of genetic diversity: population size and structure, migration, gene flow between populations.Understanding the contemporary genetic diversity of human populations - the genetic profile of the population (the population frequency of specific alleles: neutral, mutated) allows to study the genetic history of the species and reconstruct the dependence between these populations and individuals. It is also important for the diagnosis of diseases or identification of people and their population affiliation. 1. Genetic risk for rare diseases Disease occurring no more than five per 10 000 persons are referred to as rare diseases. About 80% of these diseases are genetic (have a genetic component); they also include atypical cancers and autoimmune diseases. These are chronic and severe diseases. They mostly affect children and usually lead to physical and mental disabilities (storage diseases e.g.: mucopolysaccharidosis, Gaucher disease,maple syrup urine disease - MSUD, cystic fibrosis, phenylketonuria, TaySachs disease; blood and bone marrow diseases, e.g. haemophilia, multiple myeloma; neurological diseases e.g. Huntington's disease or Huntington's chorea; immunological diseases, e.g. Chediak-Higashi syndrome and others). It is believed that each person is a carrier of about 5-10 recessive genes that are responsible for the formation of rare diseases; the cause of disease can also be gene mutations oocyte or sperm. Assessment of genetic risk of suffering from rare diseases is an essential component of genetic counselling. The information about the possibility of performing a diagnostic test should be given to those concerned before the planned pregnancy. There are many factors that influence the risk of rare diseases, such as the burden of family history, relationship between the parents, or belonging to the same ethnic group. Until recently, the diagnosis of rare diseases was based on biochemical methods - mainly recognition of the gene product can only diagnose slightly more than 100 congenital metabolic disorders. Current diagnostics of rare diseases (for more than 3,000 disease units) is possible based on the DNA analysis,i.e. identification of a mutation or analysis, in a given family, of the method of transmitting a specific genetic marker.The main feature of a marker must be its polymorphism, that is, the occurrence of more than one allele in a given locus. It can be two allelic markers - DNA sequence including single nucleotide polymorphism (SNP) recognized by a specific restriction enzyme (this type of polymorphism is referred to asthe restriction fragment length polymorphism (RFLP). The marker can also be a repetitive sequence motif – multiallelic marker e.g.: the single sequence length polymorphism (SSLP) or short tandem repeat polymorphism (STRP). 2. Dynamic mutations Mutations are phenomena of creating new alleles of a given gene or new genes. Dynamic mutations rely on multiplying the number of specific sequences (motifs) of trinucleotides (and, in some diseases, -four or -five nucleotides) within or near the sequence of causative gene, in the coding or non-coding part of the corresponding gene. The probable cause is the phenomenon of slippage of DNA polymerase - the enzyme responsible for the replication of genetic material. Exceeding a certain number of repetitions of the motif is responsible for the occurrence of the disease, e.g.in Huntington's disease, the CAG sequence is found in abnormal alleles in more than 39 replicates, in normal alleles it is found in 35 repetitions. A common feature of the majority of diseases conditioned by dynamic mutations is the occurrence of the phenomenon of anticipation. It consists of a phenomenon whereby as a genetic disorder is passed on to the next generation, the symptoms of the genetic disease are more severe and the genetic disorder becomes apparent at an earlier age with each generation. Testing the variability that reflects the rate of mutation or recombination allows haplotype analysis. Haplotype is a group of closely-coupled alleles of different genes lying in one chromosome and inherited together as a block of DNA; also referred to as a system of multiple polymorphic position (e.g. SNP, microsatellite sequences) in a given chromosome. Its analysis allows to trace the sequence genealogy and determine the order in which new alleles appear in particular positions. It provides information on the age and relationship of haplotypes. 3. Genetic population profile and complex diseases Complex diseases are diseases in which aetiology, genetic, epigenetic and environmental factors are important. Cancer, type 2 diabetes, obesity, cardiovascular diseases (e.g. hypertension, coronary heart disease), asthma, some forms of infertility, osteoporosis - these are examples of such complex diseases. Hypothesisof common disease – a common variant says that these diseases are the result of the action of many genes with small effects and therefore they are conditioned by alleles also occurring with the significant frequency in the healthy population. This makes it difficult to identify genes involved in shaping the phenotype. Also, the cooperation of rare alleles of susceptibility in many loci, often with a limited, as a result of mutation, genetic drift or selection of regionally acting, geographical occurrence, can cause such diseases. Population studies aimed at understanding the genetic background of complex diseases are based on comparing groups of unrelated healthy and ill people with respect to the coexistence of symptoms of the studied pathology and the presence of specific genetic markers (genetic diversity profile analysis, population coupling disequilibrium profile, SNP polymorphism study and environmental condition assessment). References: 1. Campbell, J.B. Reece: Biology. Pearson, Benjamin Cummings, Seventh Edition 2005 2. OMIM - Online Mendelian Inheritance in Man®, An Online Catalog of Human Genes and Genetic Disorders, Updated May 7, 2018. 3. Tepper B.J., White E.A., Koelliker Y., Lanzara C., d'Adamo P., Gasparini P. Genetic variation in taste sensitivity to 6n-propylthiouracil and its relationship to taste perception and food selection. Ann N Y Acad Sci. 2009,1170: 126-139.