The Double Helix

For information transfer in living material, specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material The continuity of life is based on heritable information (in the form of DNA). The combination of unity and diversity can only be understood in light of evolutionary processes

Molecular Biology

our understanding of: • the origins of living organisms • human evolution • variations in human behaviour • the causes of human diseases and mental health disorders

Chromatin

combination of DNA and proteins that make up the contents of the nucleus of a cell. Chromatin condenses into chromosomes

chromosome

Each chromosome contains a single continuous piece of DNA.

Genome

Equals the sequence of one full copy

Components of DNA

Four nucleotide types: Adenine Guanine Cytosine Thymine

Hydrogen bonds (electrostatic)

Adenine forms a bond with Thymine Cytosine bonds with Guanine

Replication

DNA replication is semi-conservative. In replicating, one half of the old strand is kept in the new strand. This reduces copy errors

The Central Dogma of Molecular Biology

information cannot be transferred back from protein to either protein or nucleic acid

RNA: Ribonucleic acid

Transfer the genetic code needed for the creation of proteins from the nucleus to the ribosome RNA strands are continually made, broken down and reused.

DNA

Long-term storage and transmission of genetic information DNA is protected in the nucleus, as it is tightly packed

RNA codon table - Marshall Nirenberg

4 bases, 3 per codon = 43 = 64 codons, 20 amino acids UUU - phenylalanine AAA - lysine CCC - proline

Amino Acid Structures

20 amino acids are encoded directly by the codons of the universal genetic code

Protein Structure

Proteins are polypeptides of 70-3000 amino-acids • This structure is (mostly) determined by the sequence of amino- acids that make up the protein

Effect of an Amino Acid Change

What is a Gene

A union of genomic sequences encoding a coherent set of potentially overlapping functional products.

Alternative Splicing

A regulated process during gene expression that results in a single gene coding for multiple proteins (~95% of multi-exonic genes in humans). Allows the human genome to direct the synthesis of many more proteins than would be expected from its 20,000 protein-coding genes

Mutation within chromosome

The ultimate cause of diversity in the genome Covers a broad variety of events that vary in scale, cause, and phenotypic effect – neutral: no readily discernible effect on the phenotype at the time they occur – deleterious: to greater or lesser extents, may be eliminated by natural selection – beneficial: increasing an organism’s fitness in its present environment, expect such mutations to spread in the population

actors Affecting Genetic Diversity

If a new mutation (a new allele) in a population is neutral (being neither advantageous nor deleterious), then its fate is determined by random genetic drift In the absence of selection, allele frequencies in large populations change only slowly over generations (left). In small populations, the stochastic nature of reproductive processes means that alleles may be lost or fixed within a few generations (right).

Bottlenecks and Founder Effects

A reduction in effective population size, whether because of reduction in total population size by, for example, disease (a bottleneck) or because of isolation of a subpopulation (founder effect),will reduce genetic diversity. • Subsequent population expansion is derived from only a small sample of the genetic diversity present in the original population

Classes of Sequence Variation

Single nucleotide polymorphisms (or SNPs), Insertions or deletions of one or more nucleotides (indels), Variable number of tandem repeats (VNTRs): – changes in the number of repeat sequences arranged in tandem (next to each other) arrays Presence or absence of transposable elements, Structural polymorphism – including segmental duplications and copy- number variants (CNVs)

GWAS Revisited

Most sequence variations associated with mental health disorders represent very small effect sizes.

Schizophrenia as an Exemplar

Is it a specific disease with a common biological origin? – Diversity of symptoms used to classify “delusions, hallucinations, loosening of associations, disorganised speech and behaviour, illogical thinking, social isolation, cognitive deficit – Two individuals can be classified as schizophrenic with completely different symptoms The differences may be due to many genetic variables (sequence variations), each with a tiny effect.

More Generally

Or, common disorders may be due to much rarer variations with very powerful effects There is also great variability in the penetrance of single genes, due to: – different mutations having different effects on the resulting protein – effects of other gene variants in an individual – unique environmental influences to which an individual is exposed we have, in truth, learned nothing from the genome other than probabilities. How does a 1 or 3 percent increased risk for something translate into the clinic? It is useless information.” Craig Venter

Schizophrenia Again

Black people of Caribbean origin living in Britain are nine times more likely to be diagnosed than white people (Pinto et al., 2008) – is this a genetic difference in susceptibility? • Incidence among black people in the Caribbean similar to British whites – racism may be a key factor (i.e. in Britain) • in diagnoses, and providing triggers for the condition – or, related to differences in social/family structures in immigrant communities

DNA in Context

DNA does nothing outside the context of a cell Regulation of how the “code” is read from the gene is a complex process, subject to many influences in addition to the DNA • Genes are not simply programs

Genes in Context

The triad of genes, development and environment is responsible for the adult phenotype of an individual organism. Developmental plasticity is the capacity to adjust the phenotype arising from a single genotype by changing pathways of development in early life. Developmental plasticity can be an important source of evolutionary novelty.

Summary

The human genome varies by about 0.5% between individuals arising from SNPs, insertions, deletions, inversions, and duplications of longer sequences. Only a small proportion of sequence variation causes detectable phenotypic change Genetic susceptibility to mental health disorders probably arises from: - the combined effects of numerous alleles contributing to risk, each having small effects, - or, rare alleles exerting very powerful effects (high penetrance) - coupled with the influence of environmental and developmental factors