GE Blok 1.docx

GE Interplay – Study Guide Block 1 Lecture 1: Mattering + History Behavioural genetics continues to flow beyond psychology and psychiatry into other fields: Neuroscience Economics Political science Education Sociology Including genetics in research got easier (just saliva to get from participants),...

GE Interplay – Study Guide Block 1 Lecture 1: Mattering + History Behavioural genetics continues to flow beyond psychology and psychiatry into other fields: Neuroscience Economics Political science Education Sociology Including genetics in research got easier (just saliva to get from participants), cheaper (costs of genotyping), and the stats tools better (like GWAS and polygenic scores) Behavioural genetics is also becoming more relevant to society and a part of public discourse. In the ancient world, it was discussed by Pythagoras and Aristotle that parents pass on characteristics to offspring. Pythagoras suggested that the father supplies the essential characteristics (“form”) and the mother supplies the material building blocks. Aristotle thought children were made from “purified blood from the testes” (semen) and menstrual blood. Scientists Antonie van Leeuwenhoek (1632 – 1723) and Nicolaas Hartsoeker (1656 –1725), two Dutch scientists invented the microscope and started the field of microbiology. They developed/refined the Theory of Preformationism: we all come from miniature versions of ourselves. Sperm contain completely preformed individuals called “homunculus". Francis Galton He focused his studies on the inheritance of mental characteristics and psychometrics. The closer the family relatedness, the higher the incidence of individuals with high mental ability: “a higher number of extremely able individuals are found among relatives than expected by chance”. He developed apparatus and procedures and then turned to statistics where founded the concepts of median, percentiles, and correlations. Galton introduced the use of twins to assess the roles of nature and nurture setting the essence of the twin method. It was thought to be the natural and logical extension of Darwin’s work. He stated that nature prevails enormously over nurture. He suggested that heredity underlies behavioural variation. Galton’s box911) He understood that evolution depends on heredity, and he began to ask whether heredity affects human behavior. He invented correlation. Family studies by themselves cannot disentangle genetic and environmental influences. His work was both a product and a cause of the advances that were made. He is considered the father of behavioral genetics. Charles Darwin His major input was the book On the Origin of Species after his voyage around the world to observe remarkable adaptations of species to their environment (big discoveries in the Galapagos). The theologists argued these differences were evidence of the Creator’s wisdom and asked Darwin to “prove” it. However, Darwin realized that species were not designed once and for all and stated the heretical theory that species evolve one from another. The theory of evolution begins with variation within a population partially due to heredity. It can be summarized as “all species arose through the natural selection of small, inherited variations that increase the individual's ability to survive and reproduce”. If the likelihood of surviving and reproducing (because survival is not enough) is influenced partially due to a slight degree by a particular trait, the offspring of the survivors will show more of the trait to a point those changes are so great that populations become different species. It implies 2 main points: It is difficult to know the mechanism driving evolutionary changes. Although behavior is not as well preserver as physical characteristics, it is likely that behavior is often at the cutting edge of natural selection. Darwin’s theory had serious gaps because the mechanism of heredity (gene) was not yet understood until Mendel provided the answer. However, Darwin’s theory is still highly relevant to the study of behavior. Pre-mendelian concepts of heredity and variation Heredity Substantial evidence of importance although laws unknown. Things were known by observation (breeding, sons...). Darwin’s provisional hypothesis of pangenesis: Gemmules, miniature replicas of the parents’ cells were presumably thrown off by each cell in the development. In embryogenesis, these already thrown gemmules will come into play at the proper times to make the same organ as the parents. Variation Without heritable variation in each generation, evolution could not continue. Blending hypothesis: Half of the parents create a middle point in the offspring, which will cause that variation will be reduced each generation. There are 2 ways variability is induced and, in both, the environment altered stuff of heredity (gemmules reflect the changes). They were ignorant and they knew it. Summary Long past but short history of behavioural genetics. It began with Darwin, Galton, and Mendel. Darwin’s theory caused an impact on scientific thinking. Galton studied the inheritance of mental characteristics and stated the nature-nurture problem. Lecture 2: Mendel’s laws + Exceptions to the 2nd law What we know as family trees are called pedigrees when they reflect the presence or absence of a trait. These are the symbols used to describe the members. Mendel’s laws Mendel’s first law of heredity Gregor Mendel studied inheritance in pea plants concluding: There are 2 “elements” of heredity for each trait in each individual which are separated during reproduction. Offspring receive one of two elements from each parent. One of these elements can “dominate”. The non-dominant (recessive) is only expressed if both elements are recessive. These conclusions are the essence of the law of segregation. After 30 years, his work was recognized as a general law of inheritance. The “elements” are now called genes. They can have only 1 form or more than one, which are called alleles. The combination of these alleles is called genotype and it determines the phenotype (the observed traits). Punnett square It is a diagram used to predict the genotypes of a cross or breeding experiment. Useful to determine the probability of an offspring having a particular genotype. Dominant Allele (Upper case “B” or any other letter): an allele that expresses its phenotypic effect even when heterozygous with a recessive allele. So, if B is dominant over b, then BB and Bs have the same phenotype. Recessive Allele (Lower case “b” or any other letter): an allele whose phenotypic effect is not expressed in a heterozygote. It is only expressed when homozygous, like if b is recessive over B, only ss would show the recessive phenotype. Mendel’s box (1822-1884) Before Mendel the result of crossing plants was usually sterile, and the features are complexity determined. Mendel’s success can be attributable to the absence of these problems Different varieties of the same species. Simple features due to single genes. Complete dominance. Seven years, 28000 pea plants, 1 genius 7 qualitative traits “Experiments with plant hybrids” is the cornerstone of genetics. The inheritance of one trait is not affected by the inheritance of another Not lucky in acknowledgment, he was ignored for 35 years. He died without knowing the impact of his experiments. Carriers’ box Hardy-Weinberg equilibrium (HWE): the frequency of alleles and genotypes do not change across generations unless forces such as natural selection or migration change them. Population genetics study the forces that change allelic frequency. o The frequency of dominant (p) and recessive (q) alleles are also the chances of those alleles in the population: Chances of fertilization with some allele p2or q2 (called homozygous dominant/recessive) Chances of heterozygous is 2pq The offspring genotypes expected is p2+2pq+q2 If only 2 alleles→ p+q=1 Mendel’s second law of heredity The inheritance of one gene is not affected by the inheritance of another gene. This is Mendel’s law of independent assortment. Genes are not just floating around in eggs and sperm. They are carried on chromosomes in the nucleus of the cell. Genes are located at places called loci. Eggs contain just one chromosome from each pair of the mother’s set of chromosomes, and sperm contain just one from each pair of the father’s set. An egg fertilized by a sperm thus has the full chromosome complement, 23 pairs in humans. Crossed true-breeding parents that showed the dominant trait for both A and B with parents that showed the recessive forms for A and B. He found second-generation (F2) offspring of all four possible types with the expected frequencies if A and B were inherited independently: Dominant for A and B. Dominant for A and recessive for B. Recessive for A and dominant for B. And recessive for A and B. Mendel’s law is violated, however, when genes for two traits are close together on the same chromosome. These violations make it possible to map genes to chromosomes. Recombination happens an average of one time for each chromosome during meiosis. The probability of recombination between two loci on the same chromosome is a function of the distance between them. The distance between two loci can be estimated by the number of recombinations per 100 gametes and it is called centimorgan. Linkage analysis assesses whether the DNA marker and the trait co-assort in a family more often than expected by chance. Once a gene has been found, two things are possible. First, the DNA variation can be identified. Useful to diagnose. Second, the protein coded by the gene can be studied. Of the several thousand single-gene disorders known, the precise chromosomal location has been identified for most of these genes. The gene sequence and the specific mutation have been found for at least half and increasing. Now the challenge to scientists is to discover the genetic bases of human health and disease by deciphering the genome sequence, understanding how genes work, and eventually developing medicines targeted to an individual’s genetic makeup. Key definitions: Gene: basic unit of heredity. A sequence of DNA bases that codes for a particular product. Allele: alternative form of a gene. Genotype: an individual’s combination of alleles at a particular locus. Phenotype: observed or measured traits. Dominant allele: an allele that produces the same phenotype in an individual regardless of whether one or two copies are present. Recessive allele: an allele that produces its phenotype only when two copies are present. Chromosome: A threadlike structure that contains DNA and resides in the nucleus of cells. Humans have 23 pairs. Locus (plural, loci): The site of a specific gene on a chromosome. Latin for “place.” Linkage: Loci that are close together on a chromosome and thus inherited together within families. Linkage is an exception to Mendel’s second law of independent assortment. Recombination: a process that occurs during meiosis in which chromosomes exchange parts. Mendelian disorders There are a few relevant ones. Huntington disease A brain disorder that causes progressive deterioration of the physical, cognitive, and emotional self. It leads to severe incapacitation and eventual death. It usually affects adults (30–45 years). Symptoms: uncontrollable movements, abnormal balance when walking, slurred speech, thinking difficulties, and personality changes. Dominant allele → the unaffected must have 2 normal alleles. It is maintained because its lethal effect is expressed after the reproductive years. There is no treatment, but it is possible to determine. Phenylketonuria (PKU) PKU is a metabolic disorder caused by a deficiency of the liver enzyme phenylalanine hydroxylase (PAH). It prevents the normal metabolization of phenylalanine (Phe) which is present in protein-rich foods. Damage occurs to the nervous system leading to mental retardation. Recessive allele → 2 copies are necessary to be affected, with only one, they are called carriers. The newborns are screened early to prevent retardation with dietary treatment. If you are a carrier and marry someone genetically related to you, the PKU allele must be in your family so chances are greater to have an affected child than marrying at random. Even single-gene disorders are not so simple. Many hundreds of different mutations occur and have different effects. New PKU mutations also emerge. Beyond Mendel’s laws (Exceptions to the 2nd law) The X-chromosome: An extension to Mendel’s laws Color blindness occurs more frequently in males than in females. Genes on the X-chromosome: Sex chromosomes differ in males (XY) and females (XX). Color blindness is a recessive allele on the X chromosome so males can be affected or unaffected and females affected, unaffected, or carriers if they only have one allele. The hallmark of a sex-linked trait is that the recessive gene presents a greater incidence in males. The sex chromosomes are inherited differently for males and females, so detecting X linkage is much easier than identifying a gene’s location on other chromosomes. 1500 genes have been identified on the X chromosome and a disproportionately high. number of single-gene diseases. The Y chromosome has over 200 genes and the smallest number of genes associated with disease of any chromosome. New, or de novo, mutations do not affect the parent because they occur during the formation of the parent’s eggs or sperm. But this situation is not really a violation of Mendel’s laws. Other exceptions include chromosomal abnormalities and genomic imprinting. Liability-Threshold model of disorders’ box Influenced by many genes but diagnosed as qualitative disorders. Theoretically, there should be a continuum of genetic risk One model assumes that risk, or liability, is distributed normally but that the disorder occurs only when a certain threshold of liability is exceeded. We use the liability-threshold model to estimate correlations from family risk data. This statistic refers to hypothetical constructs of a threshold. A second model assumes that disorders are actually continuous phenotypically. That is, symptoms might increase continuously from the normal to the abnormal; a diagnosis occurs only when a certain level of symptom severity is reached. A method called DF extremes analysis can be used to investigate the links between the normal and abnormal. Key definitions: Morbidity risk estimate: the chance of being affected during an entire lifetime. Correlation: an index of the relationship between two variables. Polygenic: influenced by multiple genes. Genetic relatedness: the extent or degree to which relatives have genes in common. First-degree relatives of the proband (parents and siblings) are 50 percent similar genetically. Second-degree relatives of the proband (grandparents, aunts, and uncles) are 25 percent similar genetically. Third-degree relatives of the proband (first cousins) are 12.5 percent similar genetically. Liability-threshold model: a model that assumes that dichotomous disorders are due to underlying genetic liabilities that are distributed normally. The disorder appears only when a threshold of liability is exceeded. Sex-linked (X-linked): a phenotype influenced by a gene on the X chromosome. X- linked recessive diseases occur more frequently in males because they only have one X chromosome. Carrier: an individual who is heterozygous at a given locus, carrying both a normal allele and a mutant recessive allele, and who appears normal phenotypically. Summary A gene may exist in two or more different forms (alleles). One allele can dominate the expression of the other. The two alleles, one from each parent, separate (segregate) during gamete formation. This rule is Mendel’s first law, the law of segregation. Mendel’s second law is the law of independent assortment: the inheritance of one gene is not affected by the inheritance of another gene. Except if they are in linkage disequilibrium, which allows us to map genes. These laws do not explain all genetic phenomena, like the X-linked traits. Most psychological dimensions and disorders show more complex patterns of inheritance than single-gene disorders. Lecture 3: DNA + Central dogma Living stuff is “just” a complex arrangement of atoms that are locally delaying entropy (second law of thermodynamics). Driving force: survival of genes. Mechanism: evolution. Selection of properties that favor survival and reproduction. DNA is the hereditary material. Describing psychology by only using physics/chemistry laws is extremely difficult (maybe even impossible!). This is why we separate the sciences into different levels of analysis. And why psychology is its own field of science. There are two big types of cells: Prokaryotes (bacteria): lack of extensive internal compartments and smaller. The DNA is in the genome in nucleoid and in plasmids that allow horizontal gene transfer. Eukaryotes (animals, plants, fungi): cells contain membrane-bound compartments including the nucleus and organelles. This is our type of cell. The DNA is in the nuclear genome, in mitochondria, and in chloroplasts (only in plants). Mitochondria has its own DNA because the organelle comes from a previous cell with its own DNA. DNA The discovery that DNA is the molecule responsible for heredity came a century after Mendel. Watson and Crick proposed a molecular structure for DNA based on the pictures of Rosalind Franklin. DNA molecule consists of two strands that are held apart by pairs of four bases that always pair in the same way by a hydrogen bond: Adenine (A) – Thymine (T) by 2 hydrogen bonds. Guanine (G) – Cytosine (C) by 3 hydrogen bonds. Each strand consists of sugar and phosphate molecules linking the sugars by a phosphodiester bond. The base with the sugar is called nucleoside. The addition of a phosphate group makes the nucleotide. If the sugar is a ribose, the molecule is a ribo nucleic acid (RNA) but if it is a deoxyribose, then it is a deoxyribo nucleic acid (DNA). Two functions make up the central dogma of molecular genetics: Replication during cell division: The DNA molecule unzips, the two strands unwind, and each strand attracts the appropriate bases to construct its complement. This way, two complete double helices of DNA are created. It is the essence of life and the essence of each of our cells. This is also how a PCR works. Transcription and translation to direct the synthesis of proteins: The DNA encodes the various sequences of the 20 amino acids (Aa) making up enzymes and other proteins. The genetic code contained in the sequence of DNA is transcribed to messenger RNA (mRNA) and translated into Aa. Every sequence of three bases is called codon. There are 64 possible triplet codons (43 = 64), but only 20 Aa. The translation of the genetic code is redundant but not ambiguous! A practical consequence of redundancy is that some errors in the genetic code (mutations!) cause only a “silent mutation” or an error that does not affect the protein. DNA vs RNA. Deoxyribose versus ribose. Thymine versus Uracil. Double-stranded versus single-stranded. RNA molecules are shorter than DNA molecules – rarely more than a few thousand nucleotides. DNA is way more stable. The code is different for any two people. There is no single human genome; we each have a different genome, except for identical twins. Splicing is the removal of introns in the processing of RNA to leave all the exons in the complete protein-coding sequence. There are 2 types of RNA: Coding RNA: transcripts of protein-coding genes, will be translated into protein. Only 4% of all RNA. Non-coding RNA: number of different functions performed by the RNA molecule itself. For example: transfer RNA and ribosomal RNA. Alternative splicing is when one mRNA is spliced to create different transcripts and therefore translated into different proteins. This is crucial. Individual DNA sequences would herald a revolution in personalized medicine in which treatment could be individually tailored rather than dependent on our present one-size-fits-all approach. Another new direction is the understanding of the human microbiome (genomes of the microbes living in our body) and the epigenome (chemical marks on our DNA that regulate gene expression). Genes do not code for behavior directly, but DNA variations that create differences in these physiological systems can affect behavior. Key definitions: Codon: a sequence of three bases that codes for a particular amino acid or the end of a transcribed sequence. Transcription: the synthesis of an RNA molecule from DNA in the cell nucleus. Translation: assembly of amino acids into peptide chains on the basis of information encoded in messenger RNA. Occurs on ribosomes in the cell cytoplasm. Chromosomes Mendel did not know that genes are grouped together on chromosomes, so he assumed that all genes are inherited independently. Mendel’s second law of independent assortment is violated when two genes are close together. This is useful to map genes. We have 23 pairs of chromosomes (46), but this number varies widely from species to species. One pair is the sex chromosomes X and Y. Females are XX and males XY. The other chromosomes are autosomes. Two kinds of cell division: Mitosis is the normal cell division in all cells not involved in the production of gametes, the somatic cells. Somatic cells are diploid, with two sets of the genome. Meiosis occurs in the sex cells producing eggs and sperm with one member of each chromosome pair. Each egg and each sperm have 1 of over 8 million (223) possible combinations of the 23 pairs of chromosomes. Crossover (recombination) occurs about once per meiosis 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, thereby reconstituting the full complement of 23 pairs of chromosomes. Germ cells are haploid, with only one set of the genome. The “Central Dogma” box Genetic information flows from DNA to RNA to protein. The DNA molecule contains a linear message consisting of four bases (adenine, thymine, guanine, and cytosine always pairing in the same way. The message is decoded in two basic steps: Transcription of DNA into a different sort of nucleic acid called ribonucleic acid, or RNA, and Translation of RNA into proteins. In the transcription process, the sequence of bases in one strand of the DNA double helix is copied to mRNA. It is single-stranded and is formed by a process of base pairing similar to the replication of DNA, except that uracil substitutes for thymine. mRNA leaves the nucleus of the cell and enters the cell body (cytoplasm), where it connects with ribosomes, the factories where proteins are built. Amino acids are incorporated into chains at the incredible rate of about 100 per second. Proteins consist of particular sequences of about 100 to 1000 amino acids. The sequence of amino acids determines the shape and function of proteins. They are subsequently altered in other ways called posttranslational modifications. These changes affect its function and are not controlled by the genetic code. Surprisingly, DNA that is transcribed and translated like this represents only about 2 percent of the genome. Key definitions: Centromere: A chromosomal region without genes where the chromatids are held together during cell division. Mitosis: Cell division that occurs in somatic cells in which a cell duplicates itself and its DNA. Meiosis: Cell division that occurs during gamete formation and results in having the number of chromosomes, so that each gamete contains only one member of each chromosome pair. Summary DNA has a double helix structure. Dual functions of self-replication and protein synthesis. DNA (4 bases)→RNA→Proteins (Aa)→Function. Genes are inherited in chromosomes. When there is linkage disequilibrium between them is because they are close enough and it is useful to map genes. We have 23 pairs of chromosomes.