Lecture 41

Prof Duncan Shaw

Genetic Variation

• Already know that genes have different alleles - how do these arise?

• Process of mutation - an alteration/change in the genetic material

• Origin:– Internal (e.g. mistakes during replication of

DNA)– External (e.g. radiation, chemicals)

• Most mutations have no effect or are harmful

Types of mutation• Non-coding - not in part of gene that codes for

protein - either no effect, or effect on gene expression

• Coding:– Synonymous - same amino acid– Missense - different amino acid– Nonsense - premature stop codon– Frameshift (deletion or insertion of bases) -

change in structure of protein

Mutagenesis

• Mutagens are chemicals (or radiation, etc.) that cause heritable alterations in DNA sequence in somatic and germ cells

• New mutations are rare - most genetic characteristics are due to inheritance from parents

• Teratogens are chemicals (or radiation, etc.) that affect development of the embryo/foetus and may cause congenital abnormalities (e.g. thalidomide)

The human genome

• Its size is 3 x 109 bp (3000Mb) for a single copy

• Contains 23 pairs of chromosomes

• About 35,000 genes

• About 1 million sites in the DNA that vary between individuals (most with no effect on phenotype)

Meiosis and Recombination

Chromosomes pair up DNA replicationChiasmata form

Recombination

1st cell division

2nd cell divisionGametes

Result: meiosis generates new combinations of alleles

How much genetic variation?• About 35,000 genes in humans

• If each gene has only 2 allelic forms (probably an underestimate), then:– Number of possible genotypes = 335,000 =

1016700

• Far more than all the atoms in the Universe!

• Essentially, we are all genetically unique (except identical twins)

Significance of genetic variation

• Some alleles directly cause rare genetic diseases e.g. Cystic fibrosis, sickle-cell anemia - called “simple” or “Mendelian” genetic disease

• Many alleles contribute to the risk (or liability) of getting a common disease with genetic component - called “complex” or “multifactorial” disease e.g. Cancer, heart disease, asthma, schizophrenia, diabetes (“polygenes”)

How can you tell it’s a disease gene?

• For simple genetic disease, can “track” the disease gene through affected families - called “linkage analysis”

• For complex disease, can test whether certain alleles are found more frequently in patients than in healthy controls - called “genetic association”

Unlinked Linked

1 2 1 1

2 1 1 1

2 1 1 1

Parents

Gametes

Offspring

1 2 1 1

1 2 1 1

1 1 2 1