Human Genetic Variation and Inheritance Patterns

Genetics and Genomics, Lecture 1. This lecture covers the spectrum of human genetic variation, types of mutations, and the major patterns of Mendelian inheritance with clinical examples.

TYPES OF GENETIC VARIATION

The human genome contains approximately 3.2 billion base pairs. Any two unrelated people differ at approximately 0.1% of their genome — around 3 million positions. This variation ranges from single nucleotide changes to large chromosomal rearrangements.

Single Nucleotide Variants (SNVs/SNPs): changes at a single nucleotide position. They can be: synonymous (silent) — the codon still encodes the same amino acid due to codon degeneracy; missense — a different amino acid is encoded, potentially altering protein function (e.g., sickle cell disease: HBB c.20A>T, p.Glu6Val — glutamate to valine in beta-globin); nonsense — introduces a premature stop codon producing a truncated protein; splice site — disrupts splicing, causing exon skipping or intron retention.

Insertions and Deletions (Indels): if not multiples of 3, indels cause a frameshift — altering the reading frame from that point onward, producing an entirely different amino acid sequence and usually a premature stop codon.

Copy Number Variants (CNVs): duplications or deletions of segments from 1 kb to several megabases. Example: PMP22 duplication (17p11.2) causes Charcot-Marie-Tooth disease type 1A.

Chromosomal abnormalities: numerical (aneuploidy) or structural. Aneuploidy arises from non-disjunction during meiosis. Trisomy 21 (Down syndrome): extra chromosome 21; intellectual disability, distinctive facies, congenital heart disease (AVSD most common), increased risk of Alzheimer disease (APP gene on chromosome 21). Turner syndrome (45,X): monosomy X; short stature, primary amenorrhoea, streak gonads, bicuspid aortic valve, coarctation of aorta. Klinefelter syndrome (47,XXY): tall stature, small testes, hypogonadism, gynaecomastia, infertility.

INHERITANCE PATTERNS

Autosomal dominant (AD): one mutant allele sufficient for disease. 50% transmission risk. Vertical transmission, both sexes affected equally, variable expressivity and incomplete penetrance common. Examples: Huntington disease (CAG repeat in HTT; anticipation), Marfan syndrome (FBN1), BRCA1/2, neurofibromatosis type 1 (NF1).

Autosomal recessive (AR): two mutant alleles required. Parents typically carriers. 25% risk from two carriers. Horizontal transmission, consanguinity increases risk. Examples: cystic fibrosis (CFTR p.Phe508del), phenylketonuria (PAH), sickle cell disease, haemochromatosis (HFE).

X-linked recessive: males (hemizygous XY) affected; females (XX) are carriers. No male-to-male transmission. Examples: Duchenne muscular dystrophy (DMD — dystrophin frameshift; Gowers' sign), haemophilia A (F8) and B (F9), G6PD deficiency.

Mitochondrial inheritance: mtDNA is maternally inherited. Heteroplasmy (mixture of mutant and wild-type mtDNA) means phenotype depends on proportion of mutant mtDNA and tissue affected. Examples: MELAS (m.3243A>G), Leber hereditary optic neuropathy (LHON).

TRINUCLEOTIDE REPEAT DISORDERS

Huntington disease: CAG repeat in HTT. Normal <35 repeats; >40 = disease (full penetrance). Larger repeats cause earlier onset (anticipation; more common through paternal transmission). Fragile X: CGG repeat in FMR1 5' UTR. Premutation 55-200 repeats (carrier females at risk of premature ovarian insufficiency); full mutation >200 repeats causes gene silencing, intellectual disability, autism features, macroorchidism. Anticipation through maternal transmission.