2.3,5 - Genetics PDF

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Genetics lecture notes...

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Bio 150/250, Spring 2018

Human Behavioral Biology

Molecular Genetics and the Mechanisms of Evolutionary Change: Implications for Behavior I. A review: 1. Is all evolutionary change adaptive? Spandrels and chance. 2. Is all evolutionary change the end product of competition? Abiotic selection (non-biological factors, e.g. weather, winters, storms – not competing with other species) and so many alternatives to come. 3. Is all evolutionary change gradualist? The next two hours. II. The genetic basis for being a good tap dancer. What exactly do genes do? III. The function of proteins 1. Enzymes, hormones, receptors, regulators…. DNA codes for proteins (amino acid sequence), which do everything (see above) DNA -> RNA -> protein (but don’t need to know about RNA here) 2. Amino acids as the building block of proteins Proteins made up of amino acids. Variation in charge properties of amino acids, causing different in shapes in aqueous fluids. Different shapes for different purposes 3. Shape is destiny: charge molecules; strings of charged molecules and regional heterogeneity of charge; charge leads to shape and shape leads to function A lot of processes about proteins fitting snugly into another – thus shape key 4. Lock and keys: the role of shape and specificity in molecular interactions IV. The synthesis of proteins and the central dogma of genetics 1. DNA structure Sequence of DNA (4 letters), comes in trios, which codes for one of 20 different amino acids, sequence of amino acids determines protein Codon has 43 = 64 possibilities, which is bigger than 20 – so more codon possibilities than number of amino acids, thus there is redundancy in the genetic code – most amino acids have more than one codon which codes for them. So some mutations have no impact 2. The genetic code, information content and specifying the amino acid sequence making up a protein 3.Crick’s central dogma: a. Information flows from DNA to RNA to proteins b. One gene specifies one protein. 4. Problems with this central dogma: a. More than one gene sequence can specify the same protein – redundancy in the genetic code. b. Sometimes information can flow from RNA back to DNA

c. One gene can specify more than one protein. V. Mutational changes in DNA sequence 1. Translating the basic tenets of Darwinian evolution into molecular terms. Evolutionary change is change in DNA sequence. Mutation is building block of evolutionary change, happens when there’s a mistake in copying from parent to child 2. Mutations: point, insertion and deletion mutations Point: change in one base pair in a codon, which could be very consequential (completely different amino acid), or somewhat consequential, or not consequential at all (same amino acid). Roughly 1:1 ratio of consequential vs non-consequential. If deviate so that everything is consequential – shows positive selection (selected for new traits). If deviate so that nothing is consequential – shows stabilizing selection (selecting for exact same version because very important the way they already were) Deletion: where one base pair is accidentally deleted, shifting everything onwards – could have huge effect, everything from there on can be gibberish Insertion: where extra base pair introduced, again could have gibberish VI. The consequences of traditional mutations 1. Changes in the efficacy with which pre-existing proteins carry out their function. 2. Unsubtle applications to behavior a. The phenylalanine hydroxylase gene in phenylketonuria (PKU) PKU disease where gene that codes for enzyme that converts toxic phenylalanine (found in food) into safe substance Single gene can dramatically affect behavior b. The testosterone receptor gene in testicular feminization syndrome. Testosterone only has effects if there’s a testosterone receptor. If gene for testosterone receptor missing, male is phenotypically female (testicular feminization syndrome; people think they’re female until puberty never hits and examined by doctor)

3. A more subtle application to behavior a. Anxiety and differing affinities of the benzodiazepine receptor. Valium example of benzodiazepine drug – controls anxiety (found naturally to) Due to variation in humans, variation in benzodiazepine receptors, variation in affinity of benzodiazepine and receptor (how tightly they bind, therefore how strongly signal is sent), variation in how effective benzodiazepine is, and thus explains variation in propensity for anxiety At some point, if all of us are slightly different, mutation no longer mutation, just variation – gene becomes polymorphic (different versions of it) VII. Small scale evolutionary changes in proteins, and classical gradualist thinking 1. The key dependency of sociobiology on gradualism. 2. Constructing evolutionary pedigrees a. FoxP2 and human language FoxP2 has something to do with human language – in parts of brain, needed for syntax etc. When families don’t have FoxP2 – big communication issues. Most animals have the same FoxP2. With humans, have 2 different versions that have been highly positively selected for, and emerged in the past 100,000 years Other examples of positive selection: in immune system, genes relevant to reproductive system, skin pigmentation, proteins that only occur in the brain b. Detecting positive versus neutral versus stabilizing selection 3. Thus, every little bit of competition makes a difference. 4. And, implicit in all of this is that genes know what they are doing. Major challenge #1: Do genes really know what they are doing? VIII. The false picture of genes as autonomous regulators 1. The vast quantities of non-coding DNA. Stretches of DNA between genes that don’t code – and 95% of DNA is non-coding (initially called junk DNA) Then found out non-coding DNA is instruction manual for how to use genes, i.e. when to turn it on and create the protein (on/off switches – means by which you activate transcription, or stop it from happening) Called promoter sequences 2. Transcription factors, and regulatory elements such as promoters. Upstream (just before genes) are the promoters, the on/off switches 3. The transcription of genes as regulated by transcription factors, and the activation of transcription factors regulated by the environment. Transcription factor plugs into promoter sequence and turns on the gene (again idea of fitting in perfectly)

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What determines what happens with transcription factors? Environment – determines activity/non-activity of genes a. Intra-cellular environment Example: transcription factors that activate when cell is low on energy, activates glucose transporter, and takes glucose out of circulation to cell – local energetic environment regulates transcription factor b. Inter-cellular environment Example: testosterone activates transcription factor – testosterone binds to testosterone receptor, which activates it and becomes a transcription cell, which goes to a different promoter, that turns on genes which makes muscle cells go bigger, i.e. build muscle c. Environment that occurs outside the organism Birth of baby – smell newborn – does something to hypothalamus, leads to production of prolactin, which results in production of milk Thus, the existence of environmentally dependent if-then clauses. What genes code for is interesting, but regulation of them, through environment, transcription factors, promoters, even more interesting An example of the complexity of this regulation: more than 70% of human genes are expressed in only some parts of the brain at only certain times in life. The central role of if-then clauses in evolutionary complexity a. The larger the genome, the greater percentage of it coding for transcription factors – the more complex an organism is genetically, the bigger percentage that is coding for regulation of genes (so evolution more about better regulation of genes than for genes themselves) More positive selection for promoters than genes themselves Rate of mutation also higher in promoters than genes themselves Critically, there are a higher rate of mutations in non-coding than in coding DNA. a. Evolution is more about the evolution of environmental regulation of genes than about genes themselves (Wilson and King) b. Same message: primate speciation and high rates of evolution of transcription factor genes

IX. Long-term environmental regulation of gene activity: epigenetics (mechanisms by which environment causes long-lasting changes in DNA regulation, freezes on or off for life – one of the ways in which childhood experiences have lifetime impacts) 1. Chromatin structure and access of transcription factors to DNA Chromatin enwraps DNA, and opens up in certain places to let transcription factors in, but sometimes openings glued shut forever 2. Gene silencing with methylation

Something binds to promoters, so no transcription factor can bind with promoter and activate gene – silences gene 3. A first pass at examples: a. Rodent mothering style and multi-generational regulation of the glucocorticoid receptor gene. Rat mothers differ a lot in mothering quality. If you have a good rat mother, causes epigenetic change and brain less sensitive to stress hormones, less prone to anxiety, depression and memory decline (stress hormone damaging to neurons). This has effect on mothering style as well – more attentive mothering style, which likely to produce epigenetic change in future generations Non-genetic inheritance or non-Mendelian inheritance: not a change in DNA sequence, but heritable change in regulation of some gene In general two ways can happen – 1) causes behavioral change that passes on epigenetic change (like example above), 2) epigenetic change in sperm/egg b. Rhesus monkey early experience and epigenetic regulation of >4000 genes Rhesus monkeys differ in anxious vs less anxious mothering (e.g. how many steps you can take away from her) – this results in epigenetic changes in 4000 genes (20% of genes – huge proportion of genes affected by mothering style) 4. A burst of epigenetic changes in promoters at the time of neurogenesis 5. Dutch hunger winter – during WWII there was a winter where all food diverted to Germany, then Allies came and liberated them and they had food again This had effect on third trimester pregnancies. The fetus learns at that point how much food there is in the world – during that winter, mother starving, fetus hungry, causing epigenetic change in pancreases. As a result fetus developed thrifty metabolism – every piece of food stored away, all salt stored away. Then had luxurious Westernized diet 20 fold increase in likelihood of adult-onset diabetes etc. If you were a second trimester fetus, or newborn, didn’t have that effect. This is something that happens during the third trimester If you’re a third-trimester fetus that becomes pregnant. The mother stores disproportionate amount of nutrition, so fetus has disproportionately little nutrition, and they get a mild version of the metabolic slowness as well. Effects decrease with each generation, but multi-generational nonetheless

Also, the role of chance in gene transcription. Stay tuned. Major challenge #2: Is the genome that you inherit what you have to work with forever after? X. The questionable stability of the genome: Transposable genetic elements Much less stable than you would guess 1. Barbara McClintock (plant geneticist) and her heresy – reported her observations from studying maize and heritability, and it was unexplainable by classical genetics, i.e. point, deletion, insertion. She said only way to explain some observations if that whole chunk of DNA jumps somewhere else – jumping genes. Everybody ignored her Then 4 decades later in her 80s, found transposons (stretches of DNA that would copy and appear somewhere else) a. Their frequency in plants Common in plants because can’t leave in response to new environment event. Stress induces transposing genes, in the hopes that by reshuffling DNA, can come up with a solution to the new environmental problem b. In invasive parasites In certain tropical diseases, new surface protein by transposing genes so that antibodies don’t work anymore That’s why certain topical diseases are chronic – can’t permanently deal with it because changes surface protein every so often c. And in the immune system Immune system might encounter new pathogen (or new version of same pathogen, see above) – induce different random transposable events in various immune cells, so hopefully something will result in new antibody that can deal with new pathogen, and then if something works, multiply Mechanism for speeding up variability so can deal with threats 2. The enzymatic bases of transposable events: transposases 3. The particularly interesting case of brain retrotransposons. a. Induction of transposable events during neurogenesis Shuffle DNA just when new neurons are created Also different parts of brain can have different DNA sequences – genetic mosaic b. Induction by mothering style Mothering style can cause shuffling of DNA c. Implication: the genome that your brain inherits is not set in stone XI. Mosaicism in the brain (and body) 1. Copy errors during mitosis

2. Why you have some of your mother’s cells and she has some of yours a. Stem cell exchange during pregnancy A few neurons have mother’s DNA, and vice versa because of exchange during pregnancy

Major challenge #3: Is evolutionary change really all about gradualism? Punctuated equilibrium XII. The challenge of punctuated equilibrium and large-scale evolutionary change 1. The fossil record and the perpetual search for missing links 2. Could the fossil record be complete? Stasis and saltation 3. Why this suggests that most sociobiological thinking is irrelevant: stasis much of the time. 4. The sociobiological rebuttal: a. Who is to say that a fossil record is complete? Evidence can be shown to be gradualist because so much interpretation b. What counts as rapid change for a paleotonologist counts as a ton of time for a biologist, allowing for gradualism ‘Rapid change’ about 10,000 years c. Paleontology is purely about form, morphology, and thus misses everything that is most interesting about evolution as it pertains to behavior. d. There’s no molecular mechanisms that could explain punctutated equilibrium.

XIII. Possible molecular bases for the “punctuated” part of punctuated equilibrium: the construction of genes, the existence of splicing enzymes, convergence and divergence in transcription factors and promoters 1. A gene is not coded for in a continuous stretch of DNA: introns and exons (actual DNA for gene). Introns: part of a DNA or RNA sequence that doesn’t code for a protein, but it is transcribed. Introns are removed in RNA splicing before protein synthesis (in contrast a promoter is not transcribed; instead, it is located upstream of the transcription start site of a gene and initiates transcription) a. The existence of splicing enzymes that allows the construction of RNA coding continuously for a protein. Cut out non-coding things, facilitate pieces coming together, and out comes protein 2. Alternative splicing: the ability to generate multiple types of proteins from the same gene, by translating the signal from only a subset of exons. Lots of proteins have modular parts, e.g. estrogen receptors (detect estrogen, but are also transcription factors and go on to bind to DNA) – has two different parts, the hormone binding domain and DNA binding domain, so gene for estrogen receptor typically has one exon coding for hormone binding part, and another coding for DNA binding part Note that this is the way to get combinatorial effects and combine various parts of the gene in different ways: alternative splicing due to spliceosomes Note that there is a single promoter sequence for spliced gene that occurs before the entre region to be transcribed 3. A transcription factor will interact with the promoters of multiple genes. Shows network of genes that get activated to respond to various transcription factors, e.g. dozens of genes have promoters that respond to inflammation and thus start inflammatory response – overlapping networks of regulation, very complex 4. Individual genes have multiple promoters responding to multiple transcription factors. 5. Individual genes have multiple promoters responding to multiple transcription factors resulting in transcription of different subsets of the exons making up a gene (in other words, different promoters producing different splice variants). 6. Approximately 75% of human genes with exons are alternatively spliced. Implications: can produce multiple types of proteins from the same gene, simply depending on which parts the splicing enzymes focus in on – combinatorial stuff where one gene can produce a lot of different proteins

XIV. Large-scale evolutionary change

1. The potential for vast amplification of small changes in DNA sequence. 2. Implications at the level of the modular construction of genes a. A mutation in a splicing enzyme can generate entirely novel proteins. b. A mutation in a single exon can lead to the altered structure of an array of proteins, thanks to overlapping genes. 3. Implications at the level of promoters a. A mutation in a promoter may alter which transcription factor activates that gene, thus changing its context of expression (there can also be changes in the number of repeats of the promoter, increasing the amount of protein made – not as interesting) Example: prairie voles are monogamous and pair-bonders, mountain voles are tournament species. Vasopressin serves as a hormone, serves as a neurotransmitter – used for bonding. Voles have sex then secrete vasopressin, which activates neurones in dopamine circuit, which is pleasurable so has re-inforcing properties. Difference between prairie voles and mountain voles comes down to difference in vasopressin receptors (monogamous prairie voles have more, mountain voles have less) – this means prairie voles get more buzz, get attached to female, want to stay together. No difference in vasopressin DNA, difference in promoter sequence. Because of one base-pair difference, transcription factor sticked better to one. Further studies showed that could take polygamous vole, switch out single base pair in promoter, and vole became monogamous. One single change in regulation of gene, change entire social system of entire species Extra copies create more potential for making the protein, e.g. for schizophrenia, associated with a number of genes but not different, just more of them, e.g. 2. in some Asian companies people have more of the genes for rice digestion 4. Implications at the level of transcription factors a. A mutation in a transcription factor may result in it inducing a novel network of genes. b. Genetic differences between humans and other primates: mostly about transcription factors 5.A mutation in a transposase can deposit novel stretches of DNA into novel regions of the genome. a. New genes b. New promoters c. New gene/promoter connections: novel if/then clauses: Moving a “is it dry out” promoter. ← Example: if it’s dry out hormone, turns on a bunch of different responses, e.g. to retain water. If there’s a different DNA binding domain – plug exon from somewhere to somewhere else. That’s a whole new if/then clause, whole new promoter recognition sequence. Could change to if it’s dry out, ovulate – now just

invested seasonal mating, so that everbody mates during dry season and give birth during the wet season Moving a “this is a relative” promoter Moving a “there’s progesterone in the bloodstream” exon Summary: preexisting protein v new protein/network Most of the time, these high-impact mutations are disastrous – make huge changes to already functional system. This means most don’t get passed on since won’t survive to reproduce – explaining stasis

XV. Another possible molecular basis for punctuated equilibrium: copy number variants 1. Gene duplication a. Multiple copies as safety nets against mutations (Alzheimer’s disease?) b. Multiple copies to increase expression c. Multiple copies to accelerate evolution d. Implicit in this is a retort to the creationist obsession with “irreducible complexity” XVI. Possible ...