Ch. 14 Human Genetics - Lecture notes 14 PDF

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14.1 Explaining Genetic Variation ● People in different parts of the world look very different ○ Northern Europe - blond and pale ○ Southern Asia - dark hair and dark skin ○ Arctic peoples - shorter and stockier than those who love in East Africa ● How genetic differences lead to phenotypic differences among humans and between humans and other primates ○ Genetic differences between humans and primates ■ Sequencing of the great ape genomes over the last decade has revealed much about this variation ○ How people vary genetically within and among societies ○ Processes that create and sustain variation ○ Describe nature of differences between people that are influenced by single genes with large effects ○ Variation in traits that are influenced by many genes ● A clear understanding of the nature and source of human genetic variation demonstrates that race is not a valid scientific construct. 14.2 How Humans Are Different from Other Apes ● Sequencing genomes provides information about genetic differences ○ In the past humans were distinguished by other species mostly on basis of morphology; fossils = only source of evolutionary change ● 2002: first cut ta sequencing a the entire human genome ● 2013: cost of sequencing had fallen by a factor of 100,000 and thousands of complete genomes had been sequenced ● Scientists working on sequencing genomes of yeast, fruit flies, mice, cats, dogs, rhesus macaques ● Human and chimp genomes = very similar ○ By aligning the human, chimpanzee, bonobo, and gorilla genomes and comparing the sequences nucleotide by nucleotide, geneticists have been able to measure the magnitude of the genetic differences between us and them ■ 1% difference = differences in about 30 million nucleotides ○ Humans and chimps differ by 1.3% ■ 5 million insertions and deletions of ibits of DNA in or out of the human genome or chimp genome ● Involve small number of nucleotides ● Most involve repetitive sequences or transposable elements (segments of DNA that move from one location to another within the genome of a single individual) ○ Humans and bonobos differ by about 1.3% ○ Humans and gorillas differ by 1.75% ○ Insertions and deletions contribute another 3% to the overall difference between the genomes of humans and the 3 great apes ● A majority of protein coding genes differ between humans and chimpanzees

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How cold a small genetic difference produce sizable phenotypic differences between humans and chimps ■ Small differences in the sequence of nucleotides can lead to big differences in the phenotype because the % of DNA that differs is not the same as the % of genes that differ ■ Important to know about the pattern of differences between chimpanzees and humans and overall magnitude ● Differences distributed evenly across all the genes in the genome vs clustered in certain parts of the genome ○ Protein coding genes can be identified in a DNA sequence by the “start” and “stop” codons that mark the beginning and end of each coding sequence ■ Geneticists identified 13.454 homologous protein coding genes in chimps and humans ● Only 29% of these have same amino acid sequences ● Among those that differ, the median number of base substitutions in two ● → even though DNA sequences between the two differ by only a small %, 71% of the proteins produced by their genes differ Only a small fraction of protein coding genes shows evidence of selection since the divergence of human and chimpanzee/bonobo lineages ○ Mutation and genetic drift could also create differences between the DNA sequences of humans and chimps ○ DNA code is redundant ■ Some nucleotide substitutions do not produce any change in the amino acid sequence of the protein that results from the gene ■ By contrast, nonsynonymous substitutions alter the amino acid sequence of proteins ■ Directional selection favors a protein that produces a particular phenotype ■ Structural genes that have been subjected to selection are expected to show fewer nonsynonymous substitutions than synonymous ones ■ Nonadaptive processes like genetic drift are expected to affect synonymous and nonsynonymous substitutions to the same extent ○ Once such positively selected genes have been identified, we want to determine when the change occurred ■ Geneticists compare sequences of humans and chimps to a more distantly related species, called the out-group ● When the out-group and the chimp re the same and humans differ, it is likely that out-group and chimp share the ancestral DNA sequence and that humans have the derived one ○ Vice versa ○ Percentage of positively selected genes is small ■ 2.7% of genes showed signs of positive selection How can lack of genetic change be reconciled with the substantial amount of phenotypic

change? ○ 1) Measuring selection by comparing synonymous and nonsynonymous changes underestimates the amount of change due to selection ■ This method assumes that the amount of evolution of a protein coding gene is proportional to the number of nonsynonymous DNA bases that differ between two species ■ However sometimes the change of one or two base pairs in a DNA sequence can strongly affect phenotype ● Small sequence changes are not usually detected by counting synonymous and nonsynonymous substitutions ○ FOXP2 gene in humans has a major impact on speech, even though human and chimp versions differ by only 2 substitutions ○ 2) Many of the big differences in phenotype may involve traits that are affected by genes at many loci ○ 3) Most of the evolutionary changes are not the result of changes in protein coding genes but changes in regulatory genes ■ However, evidence from gene expression suggests that regulatory changes may play a big role in shaping the differences between humans and other apes. ■ 184 genes that are expressed at the same time in the prefrontal cortex, the part of the brain involved in reasoning and decision making ● These genes are expressed at earlier ages in chimps and macaques than in humans ● Neoteny: retention of juvenile traits into later stages of life ● Humans are, in a sense, apes who retain juvenile characteristics into adulthood → we retain neural plasticity longer

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● Noncoding sequences show evidence of positive selection since the human-chimp split ○ Katherine Pollard, UCSF used different method to identify regions that

have experienced significant positive selection after human and chimpanzee lineages diverged → Searched genomes of mouse, rat, chimp to find DNA sequences that were at least 100 base pairs long and 96%/+ identical in all 3 taxa ■ Two rodent species are separated from chimps by about 70 my of independent evolution → these sequences must be subject to strong negative selection: selection against novel mutants that preserves the existing genotype ■ Found about 35,000 negatively selected sequences ● For each region, compared rate of change in human lineage with the average rates of change in 12 other vertebrate species ● Rates of change significantly greater in human lineage than in other lineages in 202 of these regions ■ Ranked regions by rate of change and assigned each region a label based on ranking ● HAR1 = fastest of the fast ● HAR202 = slowest of the fast ● HAR = “highly accelerated region” ○ Even though these segments do not encode the structure of proteins, they evolved very rapidly during human evolution ○ Suggests that they have been shaped by natural selection, not genetic drift ■ HAR1 = 118-base pair sequence on chromosome 20 ● Expressed exclusively in the brain, especially during development → rapid evolution of the larger and more complex human brain 14.3 The Dimensions of Human Variation ● Genetic Variation: differences between individuals caused by the genes inherited from parents ○ Variation in body weight ■ Individuals with some genotypes are predisposed to be heavier than others, even when diet and levels of activity are controlled ● Environmental variation: differences between individuals caused by environmental factors (such as climate, habitat, and competing species) on the organisms’ phenotypes ○ Variation in body weight ■ Availability of food ■ Culture ● Difficult to determine relative importance of genetic and environmental influences for particular phenotypic traits ○ Both genetic transmission and shared environments cause parents and offspring to be similar ■ Children might resemble parents because they inherited genes that affect

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fat metabolism or because they learned eating habits and acquired food preferences from their parents Important to distinguish variation within human groups from variation among human groups ○ Variation within groups: differences between individuals within a given group of people ○ Variation among groups: differences between entire groups of people

14.4 Variation in Traits Influenced by Single Genes ● By establishing the connection between particular DNA sequences and specific traits, scientists have shown that variation in some traits is genetic ● We can prove that traits are controlled by genes at a single genetic locus by showing that their patterns of inheritance conform to Mendel’s principles ○ If scientists suspect that a trait is controlled by genes at a single genetic locus, they can test this idea by collecting data on the occurrence of the trait in families ■ If the pattern shows a close fit to the pattern predicted by Mendel’s principles, then we can be confident that the trait is affected by a single genetic locus ○ Specific Language Impairment (difficulty learning to speak) illustrates strengths and weaknesses of this approach

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Pattern of inheritance of SLI in one family suggests that at least some cases of SLI are caused by a dominant allele at a single genetic locus Possible that an environmental factor causes SLI to run in families ● 1) collect data on more families → larger the number of families that fit the pattern associated with the inheritance of a single-locus dominant gene, the more confident researchers can be that this pattern did not occur by change

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2) researchers search for genetic markers that show the same pattern of inheritance → if every individual who has SLI also has a specific marker on a particular chromosome, we can be confident that the gene that causes SLI lies close to that genetic marker

Causes of Genetic Variation within Groups ● Mutation can maintain deleterious genes in populations but only at a low frequency ○ Natural selection steadily removes deleterious genes, but mutation constantly reintroduces them ■ Observed frequency of many deleterious recessive genes is about 1 in 1,000 ■ According to the H-W equations, the frequency of newborns homozygous for the recessive allele will be 0.001 x 0.001 = 0.000001 ● Only 1 in 1 million babies will carry the disease → even if the disease is fatal, selection will remove only two copies of the deleterious gene for every 1 million people born ○ Mutation rates for such deleterious genes are estimated to be a few mutations per million gametes produced, mutation will introduce enough new mutants to maintain a constant frequency of the gene ■ Selection-mutation balance: An equilibrium that occurs when the rate at which selection removes a deleterious gene is balanced by the rate at which mutation introduces that gene. The frequency of genes at selection–mutation balance is typically quite low. ● Selection can maintain variation within populations if heterozygotes have higher fitness than either of the two homozygotes ○ When heterozygotes have a higher fitness than either homozygote, natural selection maintains a balanced polymorphisms: a steady state in which both alleles persist in the population ■ Some lethal genes are too common to be the result of selection-mutation balance i.e. frequency of hemoglobin S allele is 1 in 10 in West Africa because it confers resistance to falciparum malaria in the heterozygous state ● Variation may exist because environments have recently changed and genes that were previously beneficial have not yet been eliminated ○ Some genetic diseases may be common because the symptoms they create have not always been deleterious ■ ex) Non-insulin-dependent diabetes ● In some contemporary populations, the occurrence of NIDD is very high i.e. on Nauru, more than 30% of people have 15 have the disease ● Genes now leading to NIDD beneficial in past because they caused a rapid buildup of fat reserves during periods of famine in harsh environments

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Traditionally Nauru life very difficult (famine was common). It was colonized by Britain, Australia, New Zealand in more recent times, and these influxes brought changes in residents’ lives → access to Western food and prosperity derived from island’s phosphate deposits allowed them to adopt sedentary lifestyLe ○ NIDD = common ○ Genes that formerly conferred an advantage on the residents of Nauru now lead to NIDD

Causes of Genetic Variation among Groups ● Selection that favors different genes in different environments creates and maintains variation among groups ○ Hemoglobin S is prevalent where falciparum malaria is common (tropical AFrica. Around Mediterranean Sea, southern India), and hemoglobin A is prevalent where this form of malaria is absent ○ Digestion of lactose provides another example of genetic variation maintained by natural selection ● Sequencing of the human genome makes it possible to detect selection from DNA sequences ○ Selective sweep: a process in which one allele increases in a population due to positive selection ■ Occurs when a beneficial mutation arises and then both the mutation and DNA linked to the mutation on the same chromosome spread through the population → selection leading to the spread of a favorable mutation can be detected by looking at regions of the genome in which identical long DNA sequences are common ■ Regions in which a sweep is likely to occur ● Reproductive system ○ Genes affecting the protein structure of sperm, sperm motility, gamete viability, female immune response to sperm ○ Genes show rapid evolution during the divergence of humans and chimps and may reflect ongoing male-female conflict or selection for disease resistance ● Morphology ○ Genes affecting skin color show evidence of strong selection among Europeans, and genes affecting bone development also show rapid evolution ● Digestion ○ Genes affecting metabolism of alcohol, carbohydrates, fatty acids ● Genetic drift creates variation among isolated populations

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Founder effect: form of genetic drift that occurs when a small population colonizes a new habitat and subsequently greatly increases in number. Random genetic changes due to the small size of the initial population are amplified by subsequent population growth. Overall patterns of genetic variation mainly reflect the history of migration and population growth in the human species ○ As we saw in Chapter 13, worldwide patterns of genetic variation preserve a record of these expansions. As human populations expand, local populations become genetically isolated from one another and begin to accumulate genetic differences. Expanding local populations exchange genes with their neighbors and with other populations they encounter as they expand. This gene flow tends to blur the effects of the expansion. However, if there is not too much gene flow, the present patterns of genetic variation will reflect the pattern of past migrations.

14.5 Variation in Complex Phenotypic Traits ● Because the relative importance of genetic variation and environmental variation will affect the resemblance between parents and offspring, the measure that computes the proportion of variation due to the effects of genes is referred to as the heritability of phenotypic traits. Genetic Variation within Groups ● Under certain conditions, measuring the phenotypic similarities among relatives, particularly twins, allows us to estimate the fraction of the variation within the population that is due to genes ○ Similarity between the environments of parents and their offspring is called environmental covariation and is a serious complication in computing heritability ○ Studies of twins → population genetic theory → useful in trying to estimate the relative magnitude of the effects of genetic variation and environmental variation on phenotypic characters ■ Compare similarity between monozygotic (identical) twins and dizygotic (fraternal) twins ■ If most of the variation in stature has a genetic origin, monozygotic twins are likely to be more similar to one another than dizygotic twins because monozygotic twins are genetically identical ■ If more of the variation is due to the environment, the similarity between parents and offspring is due to having a common family environment, then monozygotic and dizygotic twins will be equally similar ■ Suggest that about 80% of variation in height in European populations is due to genetic similarities between parents and their children ■ Heritability of height in Africa and India is about 0.6 ● Genomewide association studies confirm that height is affected by many genes, each with a small effect ○ → Look for statistical associations between phenotypic traits (e.g., stature) and a

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very large number of genetic markers located throughout the genome. An association between a particular marker and a phenotypic trait indicates that a gene near that marker affects the trait. SNP chips are used to examine the genetic basis of complex characters ■ Hundreds of thousands of short DNA segments are bound to each silicon SNP chip ■ Each of these segments matches the sequence surrounding one allele of a known SNP ■ A sample of an individual’s DNA is chemically chopped into small pieces and applied to the chip; the DNA bits bind to the matching segments on the chip ● Molecular biologists can assess an individual’s genotype at a half a million SNPs at the same time Use data to study genetic basis of complex characters ■ To determine which genes affect height, sample a large number of individuals. Measure the height of each individual and assess his or her genotype for a large number of SNPs. Then determine which SNPs are most often found in tall people and which are more often found in short people. These SNPs are either part of the DNA sequence of a gene that affects height or closely linked to such a gene. Thus, by studying the DNA sequence surrounding the SNPs, geneticists can identify genes that influence height. 180 genes affect height ■ Gene with the biggest effect leads to only a 4 mm increase in height

Genetic Variation among Groups ● Stature varies among human populations ○ Groups of people collectively vary in certain characteristics ■ People from nw Europe tall (1.75m) vs people in Italy and s Europe are about 12 cm shorter on average ● Some of the variation in body size among human groups appears to be adaptive

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○ The fact that variation within populations has a genetic component does not mean that differences between groups are caused solely by genetic differences Genomewide association studies indicate that some of the variation in stature is due to genetic differences ○ On average “tall” alleles are a little more common in northern European populations and the “short” alleles are a little more common in southern European populations → the difference in stature between these two populations is in part due to small genetic differences at a large number of loci The increase in stature that coincided with modernization is evidence for the influence of environmental variation on stature

○ 14.6 The Race concept ● The common view of race is bad biology → 3 fundamentally flawed propositions ○ 1) The human species can be naturally divided into a small number of distinct races ○ 2) Members of different races are genetically different in important ways, so knowing a person’s race gives you important information about what he or she is like. ○ 3) The differences between races are due to biological heritage. ● Because people vary, it is possible to create classification schemes in which similar peoples are grou...