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Lecture Notes Genetics in Neuroscience
This document contains all content discussed during the lectures. Each slide of the presentations is discussed and explained.
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LECTURE NOTES -GENETICS IN
NEUROSCIENCE
Claire Snel
Master Biomedical Sciences – Track
Neurobiology – Year 1 – 2024
,Inhoudsopgave
Lecture 1 – From heritability to functional experiments .................................................................. 2
Lecture 2 – GWAS and quality control ............................................................................................ 9
Lecture 3 – Interpreting GWAS and biological annotation ............................................................... 26
Lecture 4 – Genetic architecture of traits and diseases .................................................................. 42
Part 1 – Genetic architecture and genetic correlations ......................................................................42
Part 2 – Genetic risk prediction, consumer DNA testing, the ‘gay GWAS’ ............................................50
Genetic risk prediction ............................................................................................................... 50
Consumer DNA testing ............................................................................................................... 55
The ‘gay’ GWAS .......................................................................................................................... 56
Lecture 5 – Aggregating and interpreting genetic associations ....................................................... 58
Appendix 1 – Unix commands practical 1 and 2 ............................................................................. 74
1
,Lecture 1 – From heritability to functional experiments
Learning objectives
- Understand heritability and how it is estimated
- See the connections between heritability studies, gene identification, and functional
experiments
- Understand the processes underlying (Mendelian) inheritance
- Identify the main challenges in genetics research of neuropsychiatric traits
The field of human genetics
- Rapid changes in past decades
o New technologies
o Novel methods
o Large scale collaborations
o Novel disease insights
- Very brief overview of the field and link between genetics and
neuroscience: from twin studies to induced pluripotent stem
cells
Why are we all di;erent? What makes family members alike?
Nature versus nurture
Ø Are people diHerent from each other because of their genes of because of their
environments?
Ø Why are these diHicult to disentangle whether it is nature or nurture?
o Because they influence each other
o Hard to study only one, since you can’t take away the environment
o Most challenging reason: people who are genetically similar also share same
environment
Twin studies
- Twin studies, two diHerent types of twins: allows to separate genes from
environment
o Monozygotic (MZ) twins – share 100% of their genes (G) and 100%
of their common/ family environment (C), 0% of their unique
environment (E) > rMZ = 1*G + 1*C
o Dizygotic twins – share 50% of their genes (G) and 100% of their
common/ family environment (C), 0% of their unique environment
(E) > rDZ = 0.5*G + 1*C
o Compare dizygotic and monozygotic twins to compare genes,
since both have the same environment, to measure influence of genes
o Estimate contribution of genetics, environment to trait/ disease we are interested
in
2
, Ø Simple math to estimate the contribution of genes vs environment
o G = 2(rMZ - rDZ)
o E = 1 - rMZ
o C=1-G–E
Ø 100% heritable?
o Similarity in MZ twins twice as high as in DZ twins:
o rMZ = 1.0, rDZ = 0.5
Ø 100% common (family) environment?
o Similarity in MZ twins equals similarity in DZ twins
o rMZ = rDZ = 1.0
Ø 100% unique (individual) environment?
o No similarity between twins
o rMZ = rDZ = 0
Heritability
Ø Heritability = proportion of trait variance between individuals that is attributable to
genetic variance between individuals
Ø Causes genetically related individuals to correlate on a trait
Ø Heritability = proportion of variance contributed to genes
Ø Heritability estimates: contacts and population specific
Reflection: What does heritability mean?
- Is heritability destiny? What does it mean for a trait to be 100%
heritable?
- When a phenotype is 0% heritable, does it mean that no genes
have any influence on it?
50 years of twin studies – Main conclusions
- All traits are heritable to some extent (average 50%) > nature and
nurture people were right, both 50%
- Influence of c2 (common environment/ shared family environment) relatively small,
remaining percentage is unique environment
- Majority of traits are consistent with a model where all genetic variance is additive
- Additive model of genetic influences = the eHects of an allele on a trait don’t act in a
recessive or dominant way, but in an additive way
Ø We can answer the question: Are traits heritable? Yes they are
o Is around 50% for most traits
o Heritability suggests that variations in genes underlie trait diHerences between
individuals
Ø Now we know that genes are involved, what is next?
Þ If a trait is heritable – look at the DNA – find the causal genetic variants
3
,Inherited variation – DNA
- 23 Chromosomes, each containing a DNA molecule
- Approximately 24,000 genes, each coding for a polypeptide chain
- 3 x 109 base pairs, completely sequenced
- How many sites diHer between two human beings??
How similar are … in their DNA? mice and humans their DNA? 87.5%, With banana: 50%, with
fruit fly 60%, with chimp: 99%, two people share 99.9% of their DNA
The 0.1% base pair sites that di;er..
Ø The 0.1% base pair sites that diHer are the genetic causes of
phenotypic diHerences between unrelated individuals explain
(part of) why genetically similar individuals are more alike
phenotypically
Ø Genetic variations can occur:
o In a gene: protein coding, regulatory region, exonic, intronic (5% of genome)
o Outside genes: regulatory, currently unknown function (95%)
Ø Genetic variations can have eHects that are (instead of G, T in DNA sequence)
o Harmless (change in phenotype, for instance hair color)
o Harmful (diabetes, cancer, heart disease, Huntington’s disease, hemophilia)
o Helpful (evolutionary benefit)
o Latent (dependent on other gene/ environmental exposure) (epistatic gene
interaction, environment-gene interaction)
o Silent (doesn’t do anything at all)
Monogenic vs polygenic disorders
Ø Monogenic disorder (mendelian)
o Influenced by one gene or one mutation
o Large eHect (highly penetrant)
o Most genetic causes already known (OMIM lists 14000 associations)
Ø Polygenic disorders/ traits
o Influenced by multiple genes, each of small eHect
o Genetic causes mostly unknown
o Often complex: caused by multiple genetic and environmental factors with
possible interaction
Reflection genetic architecture
- Why are some traits monogenic vs polygenic?
- Are neuropsychiatric traits monogenic or polygenic?
- What forces shape this architecture? Evolution
Before we can identify the causal genes we have to answer the following question: If a trait is
heritable, how are the causal genetic variants transmitted?
4
, Charles Darwin (1809-1892)
- Charles Darwin: Blending inheritance, all siblings are exactly the
average of their parents (siblings have same height, which is the
average of the parents), all oHspring have same phenotypic
variance, variation would decrease during every generation
Gregor Mendel (1822-1884)
- Gregor Mendel: Particulate theory of inheritance, crossing of
diHerent generations with each other, observing phenotypes >
genotypes underlying colors, color is not transmitted but specific
allele of mother and father is transmitted (find allele transmitted from mother and father)
>> Main point: theory of inheritance, there is a single factor that comes from each parent that
determines what the phenotype is going to look like, the combination of the two determines the
genotype which determines what the eventual phenotype will look like
Mendel’s inheritance
Mendel’s experiments with the garden pea
Mendel’s 1st law: The law of segregation
Ø Genes are discrete particles, with each parents passing one copy to its oHspring
Ø Let an alle be a particular copy of a gene > in diploids (species with 2 of each
chromosome), each parent carrier two alleles for every gene, one from each parent
Ø Each parent contributes one of its two alleles (at random) to its oHspring
o For example, a parent with genotype Aa (a heterozygote for alleles A and a) has a
50% probability of passing an “A” allele onto its oHspring and a 50% probability of
passing along an “a” allele
Segregation ratios
- Definition: the ratio of aHected to unaHected individuals
among the oHspring of a particular type of mating
Mendel’s 2nd law: The law of independent assortment
Ø 2nd law: law of independent assortment: the phenotype (and thus the genotype at one
locus) of one trait was independent of the second (if you give your child your hair color,
you not necessarily give your eye color too)
Ø When two genetic loci are very close together on one chromosome, the law of
independent assortment does not hold, why?
o Because genes are not inherited as separate protocols
5
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