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Download Phenotype/Genotype Phenotype/Genotype cont. The sickle cell
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We have been discussing genetics (as they inform our understanding of evolution (and later, conservation biology and the applications of biotechnology in agriculture) DNA/RNA Nucleotides Chromosomes Genes Mutations Alleles Genotypes/phenotypes Gene expression Dominant/recessive We can use human blood groups to illustrate a number of genetic factoids Human blood groupings: another aspect of alleles 1. Human blood types are also an example of different alleles in a population Everybody has a gene for blood type (meaning everybody has two alleles for blood type), but we don don’tt all have the same two alleles. alleles There are four major blood proteins among humans: A, B, AB and O each of which is coded for by different sequences of nucleotides which lead to different sequences of amino acids. 2. 3. 4. 5. 6. 1 2 Phenotype/Genotype The human gene pool contains three blood alleles: A, B and O A is dominant over O, B is also dominant over O (but A and B are “co-dominant”). This means that the A or B allele will always be “expressed” and can mask the effects of the O allele. S an iindividual So di id l with ith EITHER 2 A alleles ll l or 1 A and d1O will “express” (have) type A blood. An individual with EITHER 2 B alleles or 1 B and 1 O will have type B blood. An individual with one A and one B allele will have AB type blood Since O is masked by A and B, individuals with type O blood have to have two O alleles. 4 Humans, gorillas, orangs, horses, dogs, and pigs all have characteristics similar to the A, B and O alleles in their populations: So, blood “types” (and multiple alleles) appear to be characteristic of all mammals • AA and BB are referred to as homozygous dominants • OO is referred to as homozygous recessive (the equivalent of the “spirit bear”) 2 different alleles are referred to the heterozygous genotype • AB, AO or BO There is no strong evidence of a selective advantage or disadvantage to any particular blood type Is this true of all alleles NO! 7 Homozygous dominants (AA or BB) share the same phenotype as the heterozygote (AO, BO) While they “look” alike, they represent different genotypes One measure of the genetic diversity of a population is allele frequency (how many alleles are present in the entire species gene pool), recognizing that each individual in the pool can only have 2 of the possible suite of alleles. (NOTE: sometimes there is only one allele in a population and every individual in a population is homozygous with respect to that characteristic – an extremely conservative characteristic) 5 While there are a number of known HBB gene variants, sickle cell anemia is most commonly caused by the hemoglobin allele Hb S. In this allele, the amino acid valine takes the place of glutamic acid • suggesting that this characteristic appeared long ago in mammalian evolution 3 Phenotype/Genotype cont. The type of blood you have (what is expressed) is called your phenotype – what you “look” like (phaino Gk for show) The alleles controlling that expression are your genotype So there are 4 blood phenotypes: Type A, Type B, Type AB and Type O B there But h are 6 genotypes: AA, AA AO, AO BB, BB BO, BO AB and d OO 2 identical alleles are referred to as the homozygous genotype (AA, BB, OO) Locus: The HBB gene is found in region 15.5 on chromosome 11. Gene Structure: The normal and sickle allelic variants are 1600 base pairs (bp) long Protein Size: The HBB protein is 146 amino acids Does it “matter” what blood group you are? In sexually reproducing organisms (humans and many other species), chromosomes come in pairs. This means that a particular genetic characteristic is also paired (one version or allele on each chromosome) These two alleles could be the same but there could also be a different allele for the same characteristic on each chromosome. Some alleles (referred to as dominant) are always “expressed” and they “mask” the effects of other alleles (referred to as recessive) There are actually only three different blood group alleles in the human gene pool (all the genes in all humans taken together), but each of us can only have 2 of those 3 alleles. Which pair of alleles we end up with (and whether we have 2 dominant alleles, one dominant and one recessive or two recessive alleles) determines what “type” blood each of us has. 8 6 The sickle cell allele is dominant Let’s call the allele for regular hemoglobin s Let’s call the allele for sickled hemoglobin S S is dominant, s is recessive. People with two ss alleles will have normal hemoglobin hemoglobin. People with SS alleles will have crenulated red blood cells and be very ill. Before the advent of a successful medical management regime, most people died (often in utero or shortly after birth) People who are heterozygous, Ss, will have some % of crenulated cells and may experience periodic crises but will usually survive – particularly today with advantaged medical intervention 9 1 If sickle cell anemia is (or at least was) a lethal mutation, why didn’t it ‘disappear’? Logically, you would think that a mutation creating an allele that changes the shape of the red blood cell and has life-threatening consequences (the sickled form of the cell hangs p in capillaries) p ) would not “persist” p (i.e. p people p up with this condition would die young, not reproduce and eventually the allele would disappear). But this isn’t how it worked! Why is the allele still around and of major concern to people of African ethnic origin? 10 Speciation and extinction govern biodiversity Sickle Cell Anemia: practicing vocabulary The sickle cell allele is dominant • Individuals who are homozygous for normal haemoglobin (and normal red blood cells) are homozygous recessive - ss • Individuals who are homozygous dominant for the sickled haemoglogin and sickled red blood cells are SS – they express sickle cell anemia and before the advent of medical intervention they would have died. intervention, died • However, before the advent of anti-malarial drugs, individuals who were heterozygous (Ss) suffered from partial sickle cell anemia, were not well, but it turns out they were less susceptible to malarial parasites (!) Consequently, ss individuals died from malaria, SS individuals died from sickle cell anemia. However, Ss individuals suffered but many survived to reproduce so the S allele persisted and was actually selected for! (Heterozygote advantage) 11 Fig 3.6 (KR#8) 1. The vast majority of species that have lived on Earth are gone 2. The fossil record suggests that species persistence averages 1 – 10 million years 3 Extinction is a natural process (see Fig 3.6 3. 3 6 & 3.7 3 7 in KR#8) but humans are affecting its rate. 4. Evidence supports 5 past mass extinction events (losses of 50 - 95% of Earth’s extant biodiversity) 5. Many biologists believe that we are entering the 6th mass extinction event and it is being caused by humans – the concern is persistence of ecosystem services that we and all species require 13 Peter and Rosemary Grant have studied Darwin's finches since 1973 When rainfall, and thus food, are plentiful, the finches: These futuristic looking organisms lived over 530 million years ago You can see their fossilized remains at Yoho National Park in BC The Burgess Shale fossils - the world’ss most famous ancient world marine ecosystem – played an important role in understanding the complexity of evolving life systems Yet they are unrelated to any later living forms and their disappearance presents an intriguing mystery 14 However, in 1976-1977, a severe drought struck the Galapagos 16 Mutations (whether from “mistakes” or induced by mutagens) can lead to different “versions” of the same gene (alleles) While the absence of a critical protein could be deleterious, it is also possible that a new protein created by a mutation could be advantageous or have no effect what-so-ever The peppered moth, human blood types and sickle cell anemia were examples of different alleles in a population with different outcomes • the presence of different wing colour alleles turned out to be advantageous for the peppered moth when the environment changed • the mutations that lead to different alleles for human blood types (a polymorphism*) seems to be neutral • there are also different hemoglobin alleles in the human gene pool however the mutation that lead to this is deleterious: sickle-cell anemia - however, heterozygotic advantage maintains this deleterious allele in the gene pool. 12 The Case Study of Darwin’s Finches 13 species of finches found only in the Galapagos Islands and nowhere else on earth – DNA suggests these diverged from a single ancestral group of birds that arrived on the islands Some finches have stout beaks for eating seeds of one size or another (#2, #3, #6). Others have beaks adapted for eating insects or nectar. One (#7) has a beak like a woodpecker's. It uses it to drill holes in wood, but lacking the long tongue of a true woodpecker, it uses a cactus spine held in its beak to dig the insect out. One (#12) looks more like a warbler than a finch, but its eggs, nest, courtship behavior, and (most importantly) its DNA tell us it is closely related to the other finches. 15 One of the few plants to make it through the drought produces seeds with large, tough shells that are virtually impossible to open for birds with beaks smaller than 10.5 mm Sampling the birds that starved as well as those that survived showed that the birds that survived were those with larger beaks The drought caused a precipitous decline in the production of the seeds that are the dietary mainstay of a particular f h (the finch ( h medium d ground finch) The graph shows how the population of this finch species declined from 1400 to 200 on one island in the Galapagos • have a varied diet, e.g. eat seeds across a range of sizes and • show considerable variation in body and beak sizes (large beaks are better for large seeds but can handle small seeds as well as birds with smaller beaks). Mutation is a source of genetic diversity! 17 18 2 natural selection (and microevolution) at work As the population recovered after the rains returned, the average beak depth of the population was greater than before (an increase of 4–5%) 4 5%) Birds with bill sizes greater than the mean survived Birds with bill sizes less than the mean died The curve showing the distribution of beak sizes had shifted Other sources of genetic diversity 1. Cross-over: occurs during cell reproduction Two cell division processes Mitosis (cell cloning) 1. Cross-over (and recombination) 2. Sexual reproduction • Cell division that produces two identical daughter cells (the kind of cell division growth & cell replacement) p ) associated with g a. Independent assortment b. Random fertilization 3. Transposable genetic elements (transposons), “jumping genes” or “genetic instability” beak size • Meiosis (gamete or egg and sperm production) • Cell division that produces daughter cells with half the original number of chromosomes (the kind of cell division associated with reproduction or production of new individuals) a naturally occurring phenomenon that is nevertheless remarkably similar to genetic engineering technologies 19 20 When cells reproduce they have to replicate everything inside themselves including their chromosomes Meiosis: start out with one cell (with 4 chromosomes). End up with 4 cells that each have half the number of chromosomes of the original parent, i.e. 2 chromosomes This example also shows “cross-over,” a phenomenon that sometimes accompanies chromosome duplication (whether in meiosis or mitosis) and produces genetic diversity! Mitosis: start with a single cell (with 4 chromosomes) and end up with 2 cells that are identical copies (4 chromosomes each) Most cells are doing mitosis - “cloning” themselves – making more of exactly the same kind of cell in the normal process of growth or cell replacement. However sexual reproduction requires a special kind of cell reproduction (meiosis) that produces specialized egg and sperm cells. 22 Of the 4 gametes produced by meiosis in this example, 2 have a genetic sequence identical to the parent cell (ace and bdf) no bits swapped places!! But 2 of the gametes contain unique genetic sequences, unlike those of the parent cell (acf and bde) 25 Note that the word mitosis has a “t” in it for “2” ☺ 23 How closely a child resembles a parent depends upon which of these gametes are fertilized Original chromosome (genetic sequences) of a parent 21 A child created from an egg or sperm containing this chromosome will be more like one parent than a child from an egg or sperm containing this chromosome who has a unique genetic sequence 26 Notice how tiny red and blue bits swapped places? Note that the word meiosis has a “o” in it for “1” ☺ 24 Cross-over can create genetic diversity These mules are identical twins (they are the result of a single fertilized egg that divided prior to beginning embryonic growth). Mitotic cross-overs as they grew generated slightly different pigment patterns – even identical twins don’t have perfectly identical DNA, butThese we might never be able totwins find those small mules are “identical” 27 differences among the billions of base pairs 3 What’s the point of cutting chromosome number in half? 2. Sexual reproduction: independent assortment and random fertilization can also create genetic diversity Is there any pattern to how chromosome number is cut in half? Humans have 23 pairs of chromosomes in each cell of our bodies (except our egg and sperm cells) IF there were no process to cut the number of chromosomes in half, fertilization of eggs b sperm would by ld lead l d to t a doubling d bli off chromosome number! So meiosis creates eggs and sperm cells with only 23 chromosomes (rather than 23 pairs) Fertilization restores the correct number of chromosomes to 46 (23 pairs) Recall meiosis – the type of cell division that cuts chromosome number in half. 28 Human “karyotype” 1A and 1B, 2A and 2B, 3A and 3B etc. How many different “versions” of a gamete could we make with 23 pairs of chromosomes if each pair splits independently? Transposons (jumping genes) 34 Will all the starred versions end up in the same egg or sperm? * * * * * * 29 A gamete (egg or sperm) is not a new individual! We need two gametes (to restore the correct chromosome number) Each of those 8 million + gametes has an equal chance of being fertilized by one of 8 million + other gametes 8,388, 608 x 8,388, 608 = 70, 368, 744, 177, 644 Each of us is a 1 in 70 trillion event (!) 31 Similarly to cross-over, transposons can create new alleles by inserting themselves into established coding gene sequences (changing the nucleotide sequence at the locus they have just left as well as the sequence where they now reside) They can also act epigenetically - affecting the expression of genes at other loci Transposons are similar to retroviruses a fact which has lead some people to speculate that transposons came from viruses that p p host DNA and are still there! expropriated We know that antibiotic resistance is conferred by transposons that start jumping around in the presence of antibiotics (in other words antibiotics repress the “repressors”) Transposons can also jump between species (among “species” or strains of viruses or bacteria, between viruses/bacteria or to other species including humans) As we discussed in our environmental health lectures, E. coli 0157H7 appears to have acquired its virulence from a gene that “jumped” from the bacteria that causes cholera to the originally benign E. coli probably via a retrovirus NO! Each pair splits independently 30 3. Transposons or jumping genes can also create genetic diversity Gene fragments (~750 to 2500 base pairs) found in the so-called “junk” DNA have no fixed location (locus) – they can move around spontaneously, although they appear to be under the control of “repressors” that keep them reasonably quiescent These are not p part of either the genome g or epigenome, so they are still referred to as “junk” but that means we just don’t yet understand the function of this type of DNA which is neither coding nor non-coding DNA Barbara McClintock, 1902Jumping genes/transposons often appear to 1992, discovered jumping be repeated nucleotide segments (e.g. a genes in maize in 1948. She sequence of base pairs, repeated over and was awarded a Nobel Prize for over and over again) the discovery (1983) Ubiquitous (found in the genome/epigenome of every species investigated) 32 Given individual genetic diversity, what mechanisms (besides natural selection) can change allele frequencies in a population, i.e. can lead to evolution (whether micro or macro) So … genetic diversity can derive from 1. Mutation (spontaneous or induced) 2. Cross-over during cell reproduction 3 Sexual reproduction 3. • • 2 other “evolutionary” mechanisms generally accepted as forces alternative to natural selection: Independent assortment Random fertilization 1. non-random matings (sexual selection) 2. genetic drift can also change allele frequencies – in a population 4. Transposable genetic elements (jumping genes) NOTE: changes in genetic diversity are happening at the level of an individual’s genetic material! 33 35 36 4 The diversity that derives from independent assortment and random fertilization (2)23 in humans assumes random matings among individuals Individuals may choose mates in a non-random manner Under sexual selection (or active mate choice) individuals choose mates as a result of Do humans exhibit sexual selection? Why choose a mate and who chooses? Males produce millions of sperm. “Fitness” suggests they should either: Absolutely! The data are particularly clear for both visual and olfactory (pheromone ) ‘signaling’ • attempt to copulate with as many fertile females as possible or • form a pair bond if they are assured of mate fidelity • Rikowski and Grammer* compared ratings of body odour, attractiveness, and measurements of facial and bodily asymmetry of male and female subjects. • Subjects wore a T-shirt for three consecutive nights under controlled conditions. Females' eggs are few, thus females’ “fitness” suggests they should be selective: • theyy have more invested in each g gamete and in each resulting offspring • they should seek out males who will invest resources in their offspring • male/male competition (aggression) • male display and female mate choice • female/female competition • Shirts worn by males were given to females and vice versa for the ‘snift’ test, i.e. what’s your reaction to this smell? • Rated photos of the subjects for “attractiveness.” • Additionally, bodily and facial symmetry of the odor-donors were measured. Since the availability of eggs is what limits reproductive success (fitness), evolutionary biology tells us that it’s generally males who compete for female attention and females who choose not vice versa Sexual selection in humans is complicated by cultural influences on “desirability” pheromones: chemical messengers sent outside the body that evoke physiological or behavioral changes in another member of the species Therefore males often have exaggerated secondary sexual traits to increase attractiveness to the opposite sex 37 The results? 38 Fitness and Genetic Load For women, facial symmetry, ‘attractiveness’ and perceived ‘sexiness’ of body odour were significantly + correlated. For men, ‘attractiveness’ and symmetry were + correlated but body odour was only important if females were in the most fertile (i.e. ovulatory) phase of their menstrual cycle. However there were distinct preference patterns: • Human pheromones are under genetic control with the particular pheromones secreted by any individual a function of the genes that code for our immune system or major histocompatibility complex (MHC – recall our lectures on environment and health!). • Humans can detect self odours (genetically similar MHC) versus non-self odours (genetically dis-similar MHC) finding non-self odours more appealing, i.e. opting for genetic diversity in a mate. Why mate with someone genetically dissimilar? 40 Each of us carries 5 to 8 lethal alleles which, if homozygous, would likely cause death. (The presence of lethal, sublethal and subvital genes in any species is expected since mutations, cross-over and random fertilizations mean not all individuals will be maximally fit.) The more lethal alleles found in a population, the greater its genetic load (The difference between the fittest genotype of a population and g fitness of that population) p p ) the average Inbreeding among individuals carrying a genetic load will increase the frequency of 2 individuals with similar deleterious alleles mating – increasing homozygosity of deleterious alleles As homozygosity rises through inbreeding, a positive feedback loop known as inbreeding depression sets in - characterized by reduced survival of offspring, low birth weights, and infertility among other things. (Anybody who breeds dogs, cats or fancy goldfish already knows this!) Random (stochastic) changes in allele frequency result from the fact that only a tiny fraction of all possible zygotes are going to become adults Remember that you (and your siblings) are random selections out of yyour p parents potential p pool p of 70,, 368, 744, 177, 644 possibilities In large populations, which particular gametes actually fertilize each other does not have much impact because the random nature of the process tends to average things out over successive generations But what if populations are small? 43 e.g. hemophilia in european royal families 41 In small populations, gene frequencies can change randomly in a process known as genetic drift Reach into a pile of pennies and pull out six. If there were five heads and one tail or 4 heads and 2 tails, you would not be particularly surprised p However if you pulled out 600 pennies, we would expect the results to be closer to 300 heads, 300 tails (e.g. we really don’t expect 400 heads and only 200 tails) In a small sample, chance can cause a departure from the expected result 2. Genetic drift: changes in allele frequency resulting from chance * Proc R. Soc. Lond. Biol Sci. 1999; 266:869-74 44 39 Queen Victoria arranges marriages for her children and grandchildren with royal families of Europe (to strengthen political ties). In Spain and Russia, the plan backfires leading to political unrest as the royal children are discovered to be hemophiliacs anti-British sentiments are fueled as the blood of Britain is considered “tainted.” (In Russia, Rasputin is believed to have come to power primarily because Czarina Alexandra was so unhinged over her hemophiliac son, Alexis.) Interestingly, this particular mutation seems to have started with Victoria as hemophilia was unknown in her ancestors. 42 In the next generation . . . This process of random fluctuation continues generation after generation, because the population has no "genetic memory" of its state Each generation is an independent event. However as an allele’s frequency decreases, it could become less likely to be sampled and a positive feedback process sets in where the allele continues to spiral down in ffrequency eq enc (assume (ass me a pop population lation of 100) 100). • • • • • 50 heads/50 tails (pull out 10: 6 heads/4 tails) Next generation: 60 heads/40 tails (pull out 10: Next generation: 60 heads/40 tails (pull out 10: Next generation: 70 heads/30 tails (pull out 10: Next generation: 80 heads/20 tails (pull out 10: 6 7 8 9 h/4 h/3 h/2 h/1 t) t) t) t) It is possible that an allele could disappear completely simply as the result of random chance. 45 5 Why might we care if drift changes allele frequencies in small populations (particularly why should we worry about the risk of allele loss)? It’s genetic diversity that allows organisms to adapt to change If environmental conditions change, the population may not have any significant ability to “respond” (evolutionarily) to the changed g conditions (if ( theyy have no underlying y g diversityy for natural selection to work on). Concern wrt genetic drift helps us understand the definition of a minimally viable population (MVP) - 50 breeding pairs and 500 individuals - is the minimum population size that is statistically “immune” to genetic drift for about 100 years (depending on generation time). To protect extant genetic diversity in perpetuity, populations need to have between 2500 and 5000 individuals. Small populations (subject to drift) can arise from founder effect – particularly of concern when we try to re-constitute a population from just a few individuals (or when only a few individuals survive some severe impact) Imagine that you and 9 other people are the only survivors of the human race (or the 10 of you end up traveling to Mars). Your group cannot possibly contain the full genetic diversity of all humans on the planet Nevertheless (assuming the group has both sexes), you could form a breeding population. After many generations there might be millions of people. But this second human race would be substantially genetically different from our current human race reflecting the genetics of the “founding” individuals. 46 • The team concluded that 75% of human genetic variation is the result of random genetic drift in small founder populations that left ancestral homelands. • Only ~25% of human genetic variation stems from other sources 47 48 Lions of Ngorongoro Crater, Tanzania • In 1962 a plague of biting flies killed almost all the lions in the park (leaving 9 females and 1 male) Thi population l ti is i geographically hi ll • This restricted to the Crater which cuts off emigration/immigration • While the population has rebuilt to approximately 125 individuals, their allelic diversity is different and much lower than that of lion populations in other locations 50 Numerous sources of genetic diversity TORREY pine (Pinus torreyana) Mutation Cross-over (and recombination) Sexual reproduction The rarest pine in the world with <10,000 individuals existing in only two populations in southern California P. torreyana may have been reduced to <50 individuals 8500– 8500 3500 years BP – likely as a result of post-glacial climate change It exhibits the lowest genetic diversity of any tree species known 52 http://news.nationalgeographic.com/news/2005/10/1018_051018_human_origins.html Examples of species that have passed through genetic bottlenecks 49 By the 1890s only about 20 survived. Elephant seals breed in harems, with a single male mating with a group of females,, so one male may have fathered all the offspring at the extreme bottleneck point. The population today has expanded to about The concern – from a biodiversity 30,000, but biochemical perspective - is the ability of this analysis shows that all population to respond to elephant seals are environmental change! virtually genetically identical. www.eco-pros.com/biodiversity-genetic.htm Ramachandran and her colleagues studied the genes of 53 indigenous populations around the world. Y chromosome diversity of humans The elephant seal was hunted almost to extinction in the 1800s Sohini Ramachandran, a doctoral candidate in evolutionary biology at Stanford University, was lead author of a study published in the November 2005 Proceedings of the National Academy of Sciences. founder effect can be important when a small group of individuals leaves to “found” a new population in a new environment but it can also be important when a catastrophic event reduces a population to a few survivors (a sub-set of original genetic diversity): the event is termed a genetic bottleneck g From a laboratory exercise designed by Bill Armstrong Founder effect/genetic drift is assumed to be the explanation for human genetic differences The concern – from a biodiversity perspective - is the ability of this population to respond to environmental change! • Independent assortment • Random fertilization How can we use this information to help conserve species (biodiversity) or the implications of (agricultural) biotechnology? Transposable genetic elements (transposons), “jumping genes” or “genetic instability” Number of mechanisms capable of changing allele frequency (evolution) Natural selection Non-random mate choice Genetic drift 53 The concern – from a biodiversity perspective is the ability of this population to respond to environmental change! 51 But before we can do that we need to understand how those organisms present at any particular time interact: “the ecological stage, the evolutionary play” in the words of G.E. Hutchinson Karen will start here next week! 54 6