Variation PDF

Variation principle of variation and it is a crucial component of Darwin's theory. More specifically → crucial for understanding Darwin's theory to appreciate that there is variation both between species and within species variation at two levels: the phenotype and th e genotype → phenotype - ob...

Variation principle of variation and it is a crucial component of Darwin's theory. More specifically → crucial for understanding Darwin's theory to appreciate that there is variation both between species and within species variation at two levels: the phenotype and th e genotype → phenotype - observable characteristics of an individual, such as its size, shape, color, internal structure, and physiological functioning → key one from the point of view of evolution, is because there is also variation in genes → Genes are not a lways identical even in members of the same species, and they differ much more markedly across species → genotype – set of genetic variants that an individual bears crucial role in giving rise to the phenotype The phenotype body consist of cells and there are different types → common structure → Ribosomes - chemical factories where substances needed in cell functioning are synthesized → Mitochondria - energy powerhouse where glucose and other fuels are broken down to release energy Eukaryote s - that is or ganisms such as animals and plants whose cells have nuclei and mitochondria → Prokaryote s - that is organisms like bacteria, many of the principles are the same but some of the details are different Cells are made of numerous different chemical compounds, in cluding a large number of different proteins → give cells their shape and structure, they form connecting tissues, they function as hormones and as antibodies, and, perhaps most importantly, they serve as enzymes, which control the many chemical reactions th at are needed for a body to function and to create or acquire the other types of molecule that it requires (notably water, fats, and carbohydrates) proteins are made up of amino acids → Amino acids - molecular building block of proteins 20 types The sequenc e of different amino acids along the chain determines what the properties of the protein will be Phenotype is determined by the properties of the proteins in its cells → These are determined by which amino acids are incorporated in what order as the protein chains are synthesized → Genes encode the amino acid recipes for particular proteins The genotype Classical genetics – 1. phase in which progress was made in inferring what genes did, but what genes were actually made of was unknown. The principles of this era nonetheless remain valid (Mendel) 2. Phase began with discovery that the DNA (deoxyribonucleic acid) molecule was the genetic material, and shortly thereafter Brit ish biologists James Watson and Francis Crick's resolution of the structure of DNA → Molecular genetics – understanding how genes actually encode and transmit information 3. Phase: genomics → techniques became available to 'read' large amounts of DNA sequence directly. This allowed biologists to describe the entire set of genetic material (the genome ) of different organisms Classical genetics and the central dogma There are particles of inherit ance passed from parents to offspring, which determine particular phenotypic characteristics (= genes ) Genes often come in alternate forms, called alleles Individuals have two copies of each gene , with one copy coming from each parent → Organisms/cells with two copies of each gene = diploid → Organisms/cells with only one copy of each gene = haploid Gens have two functions: 1. Influence physical characteristics (phenotype) 2. Genes replicate themselves to produce new cells or new individuals wit h the same genotype Central dogma - Changes in DNA sequence can lead to changes in proteins, but changes in proteins cannot change the sequence of DNA → Alterations in the genotype lead to alterations in the phenotype, but alterations in the phenotype do no t generally lead to alterations in the genotype → The flow of info is one - way : characteristics acquired in a lifetime will not be genetically transmittable Somatic and germ lines Somatic line = the cells of the body other than the gametes → making more phe notypes → Ex: cells in skin or heart → Mitosis = normal cell division process whereby a cell produces a daughter that is genetically almost identical to itself Germ lines = produces new individuals, that is the gametes → making more genotypes → Ex: sperm in males, egg cells in females → Meiosis = special cell division process that produces a haploid gamete from a diploid cell → recombination occurs during meiosis Molecular g enetics: genes are DNA nucleus of cells contains large amounts of a complex molecule called DNA → wound around proteins called histones This DNA - protein configuration assembles itself into a number of linear chromosomes → Diploids have chromosomes that come in pairs (23 Pairs → 46 Chromosomes) → Autosomes = first 22 pairs which are numbered by size and are the same in both sexes → diploid → Sex chromosome = females: XX, males: XY → haploid DNA (deoxyribonucleic acid) = long - chain molecule entailing 2 strands bound to each other and twisted around each other in a double helix → Each strand is made up of a backbone of sugars and phosphates → Along each backbone are sequences of four bases : Adenine ( A), Thymine (T), Cytosine (C), Guanine (G) → The bonds within each strand are extremely strong → covalent bonds → The bonds between both strands are weaker → hydrogen bonds → Base Pairing :A – T and C – G DNA can do: 1. Copies of itself → The hydrogen bonds between the strands can be “ unzipped ” and the bases float around and bind to each other creating a new backbone → constitute a new complementary strand 2. Makes Phenotypic Material: → The 2 strands are broken apart and a single - strand molecule called messenger RNA forms along the anti - sense strand of the open DNA → Ribonucleic acid ( RNA ) is chemically similar to DNA, but the T base is replaced by a U ( Uracil ) base that binds to an A base on the DNA → Transcription = The process of copying DNA sequences into sequences on an RNA molecule → takes place in the nucleus → Translation = The RNA then zips itself back up and is transported outside the nucleus into ribosomes that build proteins with the help of amino acids The genetic code genetic code = the mapping of codons to amino acids → A triplet of each base stands for one amino acid → triplets are called codons It is almost identical across all living beings → ex: the bases CGU will always bind to an arginine molecule → AUG initiates the process of translation → UAG , UGA and UAA indicate the end The code in general is robust to errors → Synonymous Substitutions = readi ng the third base wrongly won’t affect the amino acid sequence and are called → Nonsynonymous substitution = error in reading the first base leads to a chemically similar amino acid The genome: most DNA is not genes Non - coding : genes take up only a small fraction of the total genome → over 60% does not consist of genes But even within a gene, not all bases code for proteins! → Exons : Codons that are translated into proteins → Introns : Non - coding sequences, usually transcribed but not translated In general, there tend to be much more introns than exons and only just over 1% of the genome actually codes for proteins Non - coding DNA What is the rest of DNA? → Some may be the remains of once used genes = pseudogenes → vestigial characteristics Most non - coding DNA does not consist of pseudogenes → Transposable elements = Around 43% are near - identical copies of particular sequences → they can copy themselves into d ifferent parts of the genome → There are also shorter sequences called simple sequences repeats Short ones are called microsatellites Longer ones are called minisatellites What is the function of this non - coding DNA? → It is also transcribed into RNA and may have regulatory functions → May also enhance the genome’s evolvability (= ability to generate novel phenotypes) → Transposable elements promote the reshuffling and reduplication of genetic material during meiosis Evoluti on of genome size The number of genes tends to rise gradually with phenotypic complexity, but its rise is slower than the rise in the amount of DNA Differences due to polyploidy = organism having more than 2 copies of the genome More complex phenotypes may require more regulatory sequences → explains why the non - coding portion is expanded in complex eukaryotes Mitochondrial DNA Not only the nucleus, but also mitochondria have small genomes with around 16.500 base pairs organized i n a loop → Its mutation rate is relatively fast → It is haploid and asexually transmitted from the mother → because eggs and not sperm provide mitochondria to the developing embryo Evidence that DNA is the genetic material Prior to the 1950s, it was already kn own that DNA is a polymer of nucleotides, each consisting of three components: a nitrogenous base, a sugar, and a phosphate group Base composition of DNA varies from one organism to another Chargaff’s rules: 1. The base composition varies between species 2. Within a species, the number of A and T bases are equal, and the number of G and C bases are equal DNA Double helix ( Watson & Crick ) Human genome : 3 billion base pairs (counting just one chromosome for each pair) with about 25.000 protein - coding ge nes (one third only expressed in the brain! behavior?) 23 pairs of chromosomes → 22 pairs of autosomes → Sex chromosomes: females = XX, males = XY → Centromeres (without genes) Nitrogenous bases – adenine, cytosine, thymine, guanine → Purines – have 2 organic rings (A & G) → Pyrimidines – single ring (C & T) → Pairing : adenine - thymine, cytosine - guanine → Held together by hydrogen bonds Backbone – sugar (deoxyribose) + phosphate molecules Nucleoside = bas e + sugar Nucleotide = base + backbone Polynucleotide strand → Antiparallel – subunits run in opposite directions → 5’ end = phosphate group, 3’ end = OH - group of sugar (number of carbon) Codons = triplets of bases (64) – code for the 20 amino acids that make up enzymes/ proteins Functions – replication & synthesis of proteins Identical twins have the same genome Alternative splicing: mRNA is spliced to create different transcripts which are then translated into different proteins → Role in the generation of biological complexity → Disruption can lead to diseases Plomin, Chapter 4 Human genome project : the entire genome of all newborns w ill be soon sequenced to screen genetic problems and that eventually we will possess an electronic chip containing our DNA sequence → Can predict genetic risk We need to understand the microbiome (= the genomes of the microbes that live on and in our body) a nd epigenome (= chemical marks on our DNA that may play a part in how the human genome functions and contributes to health, behavior and disease) Proteins create the → Skeletal system → Muscles → The endocrine system → The immune system → The digestive system → Nervous system Protein shape is altered in other ways = posttranslational changes → affects function and are not controlled genetic code Chromosomes Our chromosomes are similar to great apes → they have 24 chromosomes, but 2 short o nes have been fused into one of our large ones One pair of our chromosomes are sex chromosomes Y and X (XX = male, XY = female) → All other chromosomes are autosomes Bands used to identify them At some point in each chromosome, there is a centromere (=regio n without genes, where the chromosome is attached to its new copy when new cells reproduce) P = short arm of chromosome above the centromere Q = long arm below centromere Mitosis = not gametes → somatic cells = each chromosome in the somatic cell duplicates and divides to form 2 identical cells → Meiosis = gamete cell formation in ovaries and testes = one member of each chromosome pair Crossover of members of each chromosome pair occurs once per me iosis and creates even more genetic variability When a sperm fertilizes an egg to produce a zygote, one chromosome of each pair comes from the mother’s egg and the other from the father’s sperm = 23 pairs of chromosomes Down syndrome caused by a nondisjun ction mutation of one of the smaller chromosomes (21) Trisomy of chromosome 13 die in first month and on 18 within the first year Missing a whole chromosome can be lethal, except for the X and Y chromosome Building a Structural model of DNA: Scientific Inquiry Watson and Crick deduced that DNA was a double helix through observations of the X - ray crystallographic images of DNA Franklin had concluded that DNA was composed of two antiparallel sugar - phosphate backbones, with the nitrogenous bases paired in the molecule’s interior The nitrogenous bases are paired in specific combinations: adenine with thymine, and cytosine with guanine A and G = purines → nitrogenous bases with two organic rings → 2x wider T and C = pyrimidines → single rings Replication Semiconservative model – 2 strands of the parental molecule separate and each functions as a template for the synthesis of a new complementary strand 1. Process begins at origin of replication – short stretches of DNA with a specific sequence of nucleotides 2. Helicases recognize these, attach to the DNA and start separating the 2 strands replication bubble with Y - shaped replication fork at both ends → Single strand binding proteins kee p strands from re - pairing → Topoisomerase relieves tighter twisting & strain ahead of the replication fork → Replication of DNA proceeds in both directions Lagging strand is synthesized discontinuously, as a series of segments – Okazaki fragments 3. Primase synthesizes primer – short stretch of RNA that serves as starting point (5 - 10 nucleotides long) 4. DNA polymerase III adds DNA nucleotides (= monomers) to the 3’ end of the RNA - primer → Come from nucleoside triphosphates 5. Only works continuously in 5’ 3’ direction (toward the replication fork) as polymerase can only add nucleoside triphosphates to the 3’ end leading strand (only one primer required) 6. Lagging stran d – synthesized discontinuously as a series of segments away from the fork → Okazaki fragments (each fragment must be primed separately!) 7. DNA polymerase I replaces primers with DNA nucleotides 8. DNA ligase joins backbones of Okazaki fragments The DNA replicati on complex Many protein - protein interactions facilitate the efficiency of this complex Lagging strand is looped back through the complex, so that when a DNA polymerase completes synthesis of and Okazaki fragment and dissociated, it doesn’t have far to travel to reach the primer for the next fragment, near the replication fork → Enables more Okazaki fragments to be synthesized in less time Transcription and Translation Transcription DNA RNA mRNA Synthesis of RNA using information in the DNA by RNA polym erase II → RNA : ribose not deoxyribose, uracil not thymine, one strand not two → Primary transcript – initial RNA → mRNA (messenger RNA) – carries a genetic message from DNA to the protein - synthesizing machinery of the cell Template strand – used to make copy of non - template strand/ coding strand of DNA → For any given gene the same strand is used as the template every time it’s transcribed Splicing (Pre - )RNA contains exons & introns Exon : coding part (1 - 2%) Intron : non - coding part (non - gene) transcribed but not translated → Pseudogenes : genes that have ceased to be translated (e.g. olfactory) → Transposable elements : ability to copy themselves into different parts of the DNA (long) → Simple sequence repeats : short internally repetitive sequences (shorter = microsatellites, longer = minisatellites) prone to mutations Spliceosomes remove introns to create mRNA (messenger RNA) → Carries genetic message from DNA to protein - synthesising machinery of the cell Tran slation mRNA Protein Synthesis of a protein (polypeptide) using the information in the mRNA → Change in language : monomers are amino acids rather than nucleotides Ribosomes = site of translation Initiation codons as start signal for translation (AUG = Methionine) Termination codons as stop signals for translation tRNA – binds to codon at ribosome to form amino - acid - chain Redundancy – multiple codons code for the same amino acid (protection against variation) The G enetic Code Codons – Triplets of nucleotides → 64 (that is, 43) possible code words → The genetic instructions for a polypeptide chain are written in the DNA as a series of nonoverlapping, three - nucleotide words For each gene, only one of the two DNA strands is transcribed = template strand → provides the pattern for the sequence of nucleotides in an RNA transcript → For other genes on the same DNA molecule, however, the opposite strand may be the one that always fu nctions as the template Codons = The mRNA nucleotide triplets, and they are customarily written in the 5’ → 3’ direction OR are the DNA nucleotide triplets along the non - template strand ( coding strand ) Because codons are nucleotide triplets, the number of nucleotides making up a genetic message must be three times the number of AA in the protein product Cracking the code (1960’s) The three codons that do not designate amino acids are “ stop ” signals → UAA, UGA, UAG AUG has a dual function: codes for methioni ne (Met) and also functions as a“ start ” signal Redundancy but no ambiguity → not random → codons that are synonyms for a particular amino acid differ only in the 3 rd nucleotide base of the triplet Universal → can synthesise insulin → Slight variations in the genetic code exist in certain unicellular eukaryotes and in the organelle genes of some species Eukaryotic gene expression is regulated at many stages All organisms must regulate which genes are expressed at any given time In multicellul ar organisms, gene expression is essential for cell specialization Differential gene expression Almost all the cells in an organism are genetically identical Differences between cell types result from differential gene expression , the expression of differe nt genes by cells with the same genome Errors in gene expression can lead to diseases including cancer  Gene expression is regulated at many stages Regulation of chromatin structure Genes within highly packed heterochromatin are usually not expressed Chemical modifications to histones and DNA of chromatin influence both chromatin structure and gene expression Histone modifications In histone acetylation , acetyl groups are attached to positively charged lysins in histone tails → When the lysins are acetylation their positive charges are neutralized, and the histone tails are no longer bind to neighboring nucleosomes This process loosens chromatin structure, thereby promoting the initiation of transcription The addition of methyl g roups ( methylation ) can condense chromatin; the addition of phosphate groups ( phosphorylation ) next to a methylated amino acid can loosen chromatin The histone code hypothesis proposes that specific combinations of modifications help determine chromatin co nfiguration and influence transcription DNA Methylation The addition of methyl groups to certain bases in DNA, is associated with reduced transcription in some species Can cause long - term inactivation of genes in cellular differentiation Methylation patter ns are passed on In genomic imprinting , methylation regulates expression of either the maternal or paternal alleles of certain genes at the start of development Epigenetic inheritance Although the chromatin modifications just discussed do not alter DNA se quence, they may be passed to future generations of cells The inheritance of traits transmitted by mechanisms not directly involving the nucleotide sequence is called epigenetic inheritance Regulation of Transcription modification Chromatin - modifying enzymes provide initial control of gene expression by making a region of DNA either more or less able to bind the transcription machinery Organization of a typical eukaryotic gene Associated with most eukaryotic genes are control elemen ts , segments of noncoding DNA that help regulate transcription by binding certain proteins → Control elements and the proteins they bind are critical to the precise regulation of gene expression in different cell types The roles of transcription factors To initiate transcription, eukaryotic RNA polymerase requires the assistance of proteins called transcription factors → General transcription factors are essential for the transcription of all protein - coding genes → Only a few general transcription factors ind ependently bind a DNA sequence, the others primarily bind proteins, including each other and RNA polymerase II In eukaryotes, high levels of transcription of particular genes depend on control elements interacting with specific transcription factors Enhancers and Specific Transcription Factors → Proximal control elements are located close to the promoter → Distal control elements, groups of which are called enhancers , may be far away from a gene or even located in an intron → A gene may have multiple enhanc ers, each activate at different time or in a different cell type or location in the organism → Each enhancer is associated with only that gene → Rate of gene expression can be strongly increased or decreased by the binding of proteins, either activators or re pressors, to the control elements of enhancers → Protein - mediated bending of the DNA is thought to bring the bound activators in contact with mediator proteins, which in turn interact with proteins of the promoter Two region sin the DNA must be brought toge ther in a very specific fashion for this interaction to happen → An activator is a protein that binds to an enhancer and stimulates transcription of a gene → Bound activators cause mediator proteins to interact with proteins at the promoter → Some transcriptio n factors function as repressors, inhibiting expression of a particular gene → Some activators and repressors act indirectly by influencing chromatin structure to promote or silence transcription Combinatorial Control of Gene Activation → A particular combinat ion of control elements can activate transcription only when the appropriate activator proteins are present Coordinately controlled genes in eukaryotes Unlike the genes of a prokaryotic operon, each of the coordinately controlled eukaryotic genes has a pro moter and control elements These genes can be scattered over different chromosomes, but each has the same combination of control elements → Copies of the activators recognize specific control elements and promote simultaneous transcription of the genes Mecha nisms of Post - Transcriptional Regulation Transcription alone does not account for gene expression → The expression of a protein - coding gene is ultimately measured by the amount of functional protein a cell makes, and much happens between the synthesis of the RNA transcript and the activity of the protein in the cell Regulatory mechanisms can operate at various stages after transcription Such mechanisms allow a cell to fine - tune gene expression rapidly in response to environmental changes RNA processing In alternative RNA splicing , different mRNA molecules are produced from the same primary transcript, depending on which RNA segments are treated as exons and which as introns → Regulatory proteins specific to a cell type control intron - exon choice by binding to regulatory sequences within the primary transcript mRNA degradation The life span of mRNA molecules in the cytoplasm is a key to determining protein synthesis Eukaryotic mRNA is more long lived than prokaryotic mRNA The mRNA life span is det ermined in part by sequences in the leader and trailer regions Common pathway of mRNA breakdown begins with the enzymatic shortening of the poly A tail → helps trigger the action of enzymes that remove the 5ć ap → Once removed, nuclease enzymes chew up the mRNA Nucleotide sequences that determine the lifetime are found in the untranslated region at the 3 ́end of the molecule Initiation of translation The initiation of translation of selected mRNAs can be blocked by regulatory proteins that bind to sequences o r structures of the mRNA → Alternatively, translation of all mRNAs in a cell may be regulated simultaneously Ex: translation initiation factors are simultaneously activated in an egg following fertilization Protein Processing and Degradation After translatio n, various types of protein processing, including cleavage and the addition of chemical groups, are subject to control Proteasomes are giant protein complexes that bind protein molecules and degrade them → Mutation can hinder it (e.g. cancer) Genetic variation Sexual reproduction shuffles the pack A human sperm or an egg cell only contains 23 chromosomes During the process of gamete formation, the gamete cell pairs the chromosomes of the male and female in order to get 46 chromosomes Recombination/Cro ssing - over During meiosis, the paired chromosomes in the progenitor cell line up next to one another and may exchange DNA, such that a sequence that was originally on chromosome A ends up on chromosome B and vice versa occur every time a gamete is formed and, since they occur somewhat randomly, the outcome of every episode of recombination is different probability of recombination is very variable across different parts of chromosomes and between different chromosomes. It also varies between men and women Independen t segregation and linkage The physically closer two genes are on a chromosome = the greater the degree of genetic linkage between them, since the probability of some recombination event breaking them apart is related to the distance between them The only thing that can disrupt this linkage is recombination Mutation creates genetic variation Single - base substitutions simples t type of mutation is the substitution of one base pair for another → This occurs occasionally due to what amounts to error when DNA is copied Transitions – changes between C and T or between G and A Transversions – changes between dissimilar pairs of bases like C and G or C and A Transitions occur about twice as often as transversions. Deletions of a base also occur, but these are much less frequent than the substitution of another base Rates of mutation are very much higher wherever a C is followed by a Gin the DNA sequence Simple sequence repeat expansions and contractions slightly larger type of mutation is the expansion or contraction of a simple sequence repeat In such a mutation, an extra copy of the repeat motif is added, or one lost → occurs because of 'slippage' of one repeat as the enzyme responsible for DNA replication lines itself up to the DNA strand Transposable element insertions and segmental duplications larger mutation is the copying of transposable element such as Alu from one part of the genome to another (1 in 100 human births) → depending on where the element moves to, may or may not have a phenotypic effect Segmental duplications = events were a chunk of sequence makes an extra copy of itself during replication, often but not necessarily adjacent to the original copy → Important for evolutionary change : evolution selection tends to get stuck for any gene whose primary function is in dispensable to the organism Also have segmental deletions or inversions of whole segments of sequence Duplications give extra copies of the genes involved: one sufficient to perform original function, the other one can acquire new mutations that may bring in new functions Many human genes belong to gene families = multiple genes descended from a common ancestor by duplication of events → Make similar products with subtle functional differences → allowing for complex phenotypic systems → Ex: HOX genes Whole genome duplication Rare Accounts for polyploidy and gene families Acts like a huge segmental duplication, with the 2 copies going on to have divergent evolutionary histories Point mutations = chemical changes in a single pair of a gene 1) Single nucleotide pair substitutions → Silent mutation = Some substitutions have no effect on the encoded protein, owing to the redundancy of the genetic code → no observable effect on phenotype → Missense mutation = Substitutions that change one amino acid to anothe r on → little effect on the protein The new AA may have properties similar to those of the AA it replaces Or it may be in a region of the protein where the exact sequence of AA is not essential to the protein’s function → Nonsense mutation = A point mutation can also change a codon for an AA into a stop codon → causes translation to be terminated prematurely = polypeptide will be shorter Nearly all nonsense mutations lead to non - functional proteins 2) Nucleotide pair insertions or deletions → Frameshift mutation → Alters the reading frame of the genetic message → Occurs whenever the number of nucleotides inserted or deleted is not a multiple of three → Result will be extensive missense, usually ending sooner or later in nonsense and premature termination → Unless the frameshift is very near the end of the gene, the protein is almost certain to be non - functional Mutagens = A number of physical and chemical agents interact with DNA in ways that cause mutations → X - rays or UV light → Effect: Nucleotide chemicals that are similar to normal DNA nucleotides pair incorrectly during DNA replication Interfere with correct DNA replication by inserting themselves into the DNA and distorting the double helix Cause chemical changes in bases that change their pairing properties The extent of genetic diversity and its effects on the phenotype Locus = particular site in the genome Polymorphism = a locus for which there is more than one allele in the population 2. Single nu cleotide polymorphisms (SNPs): something like one in every single 1000 single bases varies from individual to individual 3. Single sequence repeats, with their high mutation rate, are extremely polymorphic = every individual is unique → basis of DNA fingerprinting 4. Around 12% of the human genome consists of sequences of which individuals have varying numbers of copies due to recent segmental duplications. Some segmental duplications involve very long sequences, and there are 100s of genes of which different individuals have varying numbers of copies 5. In a base - by - base comparison of the 2 copies of the genome within a single hum an, at least 0.5% of the genome was different between the 2 copies Most polymorphisms have no phenotypic effect Reservoir of genetic variation from which phenotypic variation may result, but most genetic variation as no effect on the phenotype Occurs in no n - coding DNA If small, even in exons of genes → make no difference to the AA sequence due to the redundancy of the genetic code Where mutations do have a phenotypic effect, they are usually deleterious/harmful Why are most mutations harmful? Mutation is u ndirected → the effect of the mutation is unrelated to the physiological needs and functions of the phenotype → so its more likely that it will make it function less well the occasional one will arise that actually improves biological performance in the an imal's environment. These rare advantageous mutations are spread by natural selection From genotype to phenotype New non - synonymous mutation in the coding sequence of a particular gene This gives us a distinct allele of the gene → when transcribed and translated, it will produce a different AA chain → protein The protein will either: → Be an integral part of the body system → Serve as an enzyme to catalyze some other chemical reaction on the body Most genes have many functions Single - gene and polygenic characteristics Single - gene characteristics : the difference in phenotypes is determined by which allele the individual has at just one genetic locus Single - gene diseases /Mendelian diseases :c ystic fibrosis (chromosome 7) Also healthy variations: Rhesus factor Gene hunting Linkage studies useful to localize the gene underlying single - gene traits using a fairly small n° of genetic markers → Examine large families where some members have and some lack the phenotype characteristic of interest → Then establish the genotype of each individual for polymorphic genetic loci whose chromosomal location is known → Then they search the data for marker alle les that are shares by affected family members but not the unaffected ones Association studies: powerful but require many hundreds of genetic markers per chromosome → since individuals are not closely related, recombination will have thoroughly shuffled th eir chromosomal contents, so significant allele frequency differences will only be found for the gene of interest or markers that are close to it → Can either focus in on a few genes (candidate gene approach) or can cover the whole genome (whole - genome/ geno me - wide approach ) → flexible and economic → Establish 2 samples of individuals from the population: those with phenotypic characteristics of interest and those without it → The individuals are then genotyped to test for the differences in allele frequencies b etween the 2 groups Identifying alleles involved in polygenic characteristics Polygenic traits = variation in the phenotype is related to which allele is present across a n° of genes Ex: height Hard to detect using linkage and association Large samples are needed to identify the genetic influence Genes for physical characteristics Huntington’s disease : incurable neurological condition which leads to gradual loss of coordination and cognitive abilities → It’s a single - gene disease stemming fr om a disease - causing allele of a gene on chromosome 4 → codes for Huntingtin protein: 3000 AA, active in CNS, makes protein that helps keep cells alive → Huntingtin gene contains a simple sequence repeat with the motif CAG → normal copies of the gene have 11 - 34 copies of this repeat → since CAG is the codon for glutamine , after transcription and translation, Huntingtin contains a chain of 11 - 34 glutamines in a row within it → Every now and then an allele of the Huntingtin gene with 40+ repeats of the motif appe ars → will make a protein containing 40+ glutamines = will have different reactive properties (don’t break down in the same way) = don’t survive well Association study on dogs with varying sizes of the same breed (Portuguese Water Dog) → Found strong eviden ce for an association with size for a gene on chromosome 15, IGF1 → high frequency of one allele in small dogs, but absent in big dogs (Great Dane) → IGF1 codes for an insulin - like growth factor which is involved in turning on body growth Genes for behavior Animal study: Prairie voles (PV) study → Prairie voles (rodents) form long - term bonds after mating → Hormone arginine vasopressin causes a pair bond to form → released in male’s brain on mating with the female → Also produced in other rodents but prairie voles have more receptor molecules (V1a) → The gene that produces V1a has been localized → almost identical across different rodents but there is an associated regulatory sequence that’s different in PVs → Young created genetically engineered mice that had the PV version of this sequence → behavior changed Human study: Monoamine oxidase A (MAOA) gene study → Enzyme that helps regulate serotonin (mood states) → Studied a Dutch extended family in which many of the males had a severe conduct disorder (violence, rape, arson) → gene in the part of the X chromosome → These men completely lacked in MAOA activ ity → Found 4 single - base changes in the men: 3 of these were synonymous (not responsible), the 4 th was a transition from a C to a T at the 936 th base → first base of a codon, normally CAG (produced glutamine), but became TAG (stops transcription) → MAOA may b e associated with ADHD and antisocial behaviors Article: The seductive allure of behavioral epigenetics (Miller) Epigenetics could explain how early life experiences can leave a mark on the brain and influences both behavior and physical health later These ills include the long - term health problems of people raised in lower socioeconomic environments and the struggle of drug ad dicts to kick the habit The Importance of Nurturing : → The way how a rat mother nurtures her pubs influences how they respond to stress in later life → Less nurturing leads to increased methylation of the gene for BDNF (neural growth factor) or reduce glucoc orticoid receptors (Important for the immune system!) → Rats raised by less nurturing mothers tend to have more methyl groups attached to the promotor region of the glucocorticoid receptor gene block access by transcription factors fewer steroid receptor s produced (normally would’ve dialed down reactivity to stress) → Parental period : rapid changes in brain thus sensitive to quality of environment → Chronic stress triggered an increase in a type of histone methylation that suppresses gene activity by keeping the DNA containing the Bdnf gene tightly wound Experience of learning associated with rapid changes in gene - methylation in HC if inhibited then impairment of memory of that experience Antidepressant drugs can boost histone acetylation, which helps unwind DNA from histones and promote BDNF activity Epigenetic Mechanisms could also play a role in Drug Addiction in the sense that cocaine for example suppresses methylation of a particular histone in the nucleus accumbens leading to the growth of dendritic spines Studies on human brain tissue of patients that died due to suicide Socioeconomic status early in life does appear to alter gene expression Epigenetics prove a potential explanation for how social conditions can affect biology in ways that can contribute to poor health. But they’re certainly not the only factor and more research needs to be done, espec ially on humans. Article: Genes in Context (Champagne) Interactions between genes and the environment are a critical feature of development → Insights into the dynamic interplay between these factors have come from laboratory studies exploring experience - dep endent changes in gene function Cooper and Zubek published a report in which rats selectively bred to be either ‘‘maze - dull’’ or ‘‘maze - bright’’ were reared after weaning in either ‘‘enriched’’ environments containing increased sensory stimuli or ‘‘impover ished’’ environments containing limited sensory stimuli → maze - dull animals reared in an enriched environment showed a signi fi cant improvement in learning ability, and maze bright animals reared under impoverished conditions showed a signi fi cant decline in pe rformance Gene - by - Environment Effects (G x E) show that even when considering genetically derived characteristics our prediction of behavior must incorporate knowledge of the environmental context and development risk of depression was predicted by the int eraction of serotonin transporter genotype and the number of stressful life events experienced What are environments doing to genes that alter their impact? → Variations in maternal care lead to individual differences in the expression of genes that alter st ress response (low level of glucocorticoid receptors) → Studies with monozygotic twins show that there is more discordance of gene expression in older than in younger twins These studies illustrate the role of epigenetic mechanisms in shaping the activity of the genome in response to environmental cues and demonstrate the plasticity that is possible through shifts in DNA methylation Elevated levels of methylation were detected in ribosomal RNA genes among suicide victims DNA methylation may also ha ve implications for the transmission of traits from one generation to the next Experience of low levels of maternal care in infancy is associated with increased estrogen receptor promotor methylation, decreased receptor expression, and subsequent decreases in the adult maternal behavior of these offspring → thus, there is a behavioral transmission of individual differences in maternal care across generations both genetic and epigenetic factors are transmitted down cell lineages with consequences for the activ ity of genes within these lineages DNA methylation may also have implications for the transmission of traits from one generation to the next. There are two pathways through which this can occur 1. Behavioral transmission through experiences that changed with methylation 2. Environmental effects that change DNA methylation in germ cells → Experience - dependent change in the epigenetic status of genes is not limited to the postnatal period Article: From Gens to Brain to Antisocial Behavior (Raine)  Hypothesis : Specific genes result in structural and functional brain alterations that in predispose to antisocial behavior Over 100 twin and adoption analyses provided evidence that about 50% of the variance in antisocial behavior is attributable to genet ic influence Genes : But which genes predispose to which kinds of antisocial behavior? → Knocking out monoamine oxidase gene A (MAOA) causes aggression in mice → At least 7 genes to date meet the criteria of being associated with aggression (MAOA, 5HTT, BDNF, NOTCH4, NCAM, tlx and Pet - 1 - ETS) → MAOA codes for an enzyme that breaks down serotonin , a neurotransmitter that is low in antisocial individuals → Males with a co mmon polymorphism (variant) in the MAOA gene have an 8% reduction in the volume of the amygdala, anterior cingulate, and orbitofrontal (ventral prefrontal) cortex → These brain structures are involved in emotion and are found to be compromised in antisocia l individuals Brain : How does one progress from genes to antisocial behavior? → An explanation is that gene abnormalities result in structural brain changes that result in emotional, cognitive, or behavioral abnormalities, which in turn predispose to antisoc ial behavior → Especially impairments in the prefrontal cortex (reduced gray matter) can lead to an antisocial personality disorder → 11% reduction in prefrontal gray matter, together with reduced autonomic activity during a social stressor designed to elicit ‘‘secondary’’ emotions of shame, embarrassment, and guilt → These structural impairments are paralleled by functional impairments (e.g. reduced glucose metabolism that usually helps to inhibit impulses) → This impairment also speci fi cally characterizes impuls ively violent offenders, suggesting that the prefrontal cortex acts as an ‘‘emergency brake’’ on runaway emotions generated by limbic structures → Impairments are also documented in the cingulate, temporal cortex, angular gyrus, amygdala and hippocampus Antisocial Behavior : How do these impairments give rise to antisocial behavior? → Risk factors are no conceptualized as directly causing antisocial behavior but instead bias social behavior in an antisocial direction → Poor fear conditioning may re sult in a failure to fully develop a conscience — a set of conditioned emotional responses that motivate individuals to desist from previously punished behavior → Poor conscience development is in turn viewed as a predisposition to antisocial behavior. → Neural Moral Theory : Antisocial individuals have a breakdown in the neural circuit normally activated during moral decision making Areas include the medial prefrontal cortex (PFC), ventral PFC, angular gyrus, posterior cingulate, and amygdala — all areas implicated in antisocial behavior → some of the brain impairments in antisocial individuals disrupt moral emotion and decision - making turn predisposing the individual to rule - breaking, antisocial behavior Environment : From Environment to Genes to Brain to Environment? → Environmental influences early in development could change gene expression (The way in which a gene’s DNA is translated into neuronal structure) in turn altering brain functioning and resulting in antisocial behavior → Although 50% of the varian ce in antisocial behavior is genetic in origin, genes are not fixed, and psychological influences can result in structural modification → social environment can interact with genetics and biological risk factors for antisocial behavior in other ways Antisoci al behavior is exponentially increased when social and biological risk factors combine → For example, abnormality in the MAOA gene interacts with early child abuse in predisposing to adult antisocial behavior Treatment : How can the “broken” brain get fixed? → IQ mediates the relationship between poor malnutrition and antisocial behavior – changing eating habits by adding omega - 3 can reduce abnormal behavior → Environmental manipulation can in theory reverse brain risk factors → Remediating neurotransmitter by incre asing serotonin (e.g. Prozac) → raises neuroethical questions that need to be aired in order for prevention science to progress Article: Epigenetics and Development (Powledge)  Epigenetics : the study of mechanisms that change gene expression by modifying DNA without modifying its sequence of bases → may be heritable or not! → Does not involve changes to the underlying DNA sequence → A change in phenotype without a change in genotype → Affects how cells read the genes → Could explain how early life experiences can leave a mark on the brain and influences both behavior and physical health late Two processes: DNA Methylation & Histone Modification DNA methylation : tagging specific points in the DNA mol ecule with a methyl group (“DNA instructors”) that silences the genes → Its effects are also reversible, and this flexibility helps individuals to change when their surroundings change → Silencing often is inherited by daughters of the cell with the silenced g ene → All the epigenetic differences explain the phenotypic differences between species → In mammal embryos, methylation regulates DNA structure and gene expression from the earliest zygotic stages and governs developmental processes such as X chromosome inact ivation → different expression patterns and therefore different epigenetic profiles → DNA methylation differences in placental and cord blood between babies conceived in the usual way and in the lab → long - term consequences → DNA methylation matters in pre - and postnatal development Histone Modification : Histone – proteins that are the spools that DNA winds itself – can change how tightly or loosely the DNA is wound around. The chromatin structure can be chemically modified by for example adding or subtracting a methyl group → If DNA is more loosely wound → genes c an express more → If DNA is more tightly wound → restricting access to genes DNA methylation and histone modification interact with and depend on each other , even though they have somewhat opposite effects → DNA methylation can impose permanent (or at least st able) regulation → Histone modification is more labile and reversible Histones are described as spools used for winding up the DNA Chromatin is the stuff of chromosomes (made of histones and DNA) → Chromatin structure can change when histone proteins are chemi cally modified Are we what we eat? Researchers found that nutrition plays an especially important role in differentiating human’s and chimp’s phenotypes → Evidence for this theory was offered by the so - called Agouti Mouse Clone , genetically identical mice whose mutant cote turned many of them yellow. By feeding the females with food containing extra methyl groups that turn off the mutation, researchers were able to produce offspring that had a brown coat → Dutch famine: methylation of the IGF2 gene was decreased — and still remained lower — but only in those people whose mothers starved in the first three months of pregnancy; methylation was normal in people expose d as older fetuses Long non - coding RNA → Important for silencing X chromosomes in females → specify most phenotypic differences btw. & within species (regulates nearby genes) MircoRNA → Regulate gene expression by repressing or breaking up messenger RNA → Figu re in signaling and apoptosis as well as in cell differentiation and other points in development → must have evolved at the vertebrate dawn → Vertebrate complexity is due not to protein evolution but to a dramatic expansion of gene regulation by noncoding RNA, especially microRNA → Phenotypic evolution in vertebrates may have been helped by both microRNA and proteins such as signaling proteins and transcription factors → Epigenetics suggests that mechanisms operating at the earliest moments of life may influence behavior and disease decades later, may be passed onto future generations, may even help shape evolution