Human Genetics Sep 26

Genetics and Humans

Introduction to Human Genetic Analysis

Human genetics applies classical and molecular genetic concepts to understand inheritance, disease, and variation in humans. Due to ethical and practical limitations, human geneticists use indirect methods such as pedigree analysis and twin studies to infer genetic principles.

• Pedigrees: Diagrams that track inheritance of traits across generations.

• Twin Studies: Comparisons between monozygotic (identical) and dizygotic (fraternal) twins to estimate genetic and environmental contributions to traits.

Pedigree Analysis and Chromosome Mapping

Pedigree Structure and Interpretation

Pedigrees are essential tools for tracking inheritance patterns and mapping genes in human families. They help identify modes of inheritance (dominant, recessive, X-linked, etc.) and can be used to estimate genetic distances between loci.

• Symbols: Squares represent males, circles represent females, filled symbols indicate affected individuals.

• Generations: Labeled with Roman numerals (I, II, III, etc.).

• Chromosome Mapping: Genetic distances between loci (e.g., zk5358 and a mutation) are measured in centiMorgans (cM), where 1 cM ≈ 1% recombination frequency.

Example: Calculating Genetic Distance

• To determine the distance between zk5358 and a mutation:

  • Count the number of recombinant offspring (those with new combinations of alleles).

  • Count the total number of informative meiotic events (meioses where recombination could be detected).

  • Calculate recombination frequency: $\text{Recombination Frequency} = \frac{\text{Number of Recombinants}}{\text{Total Informative Meioses}} \times 100$

  • Distance in cM = recombination frequency.

• Example Arrangement: If Zg1234 is 15 cM from zk5358 but only ~1 cM from the mutation, the order on the chromosome is: Zg1234 — mutation — zk5358.

Twin Studies in Human Genetics

Principles of Twin Studies

Twin studies are a classical approach to estimate the heritability of traits in humans by comparing the similarity (concordance) of traits between monozygotic and dizygotic twins.

• Monozygotic (MZ) Twins: Arise from the division of a single fertilized egg; genetically identical.

• Dizygotic (DZ) Twins: Result from two separate fertilization events; share ~50% of their genes, like regular siblings.

Key Terms

• Concordance: The probability that both twins share a trait.

• Concordant: Both twins have (or both lack) the trait.

• Discordant: Only one twin has the trait.

Estimating Heritability

• If MZ twins show higher concordance for a trait than DZ twins, the trait is likely to have a strong genetic component.

• Example: 61% concordance for type II diabetes in MZ twins vs. 23% in DZ twins suggests a significant genetic influence.

Isolating Variables

• Twin studies attempt to control for environmental variables by comparing twins raised together.

• However, environmental and genetic factors can still vary between and within twin pairs.

Pitfalls of Twin Studies

• Environmental factors may differ even for twins raised together.

• Genetic background can vary between populations.

• Monozygotic twins may not be completely genetically identical due to de novo mutations or epigenetic changes.

• Does not identify specific genes involved in a trait.

Interpretation Example

• If MZ and DZ twins have similar concordance for a trait (e.g., blood pressure), it suggests a strong environmental influence or a trait with low heritability in that context.

• Differences in concordance between studies may reflect population differences or environmental variation.

De Novo Mutations in Human Genetics

Types and Origins of Mutations

De novo mutations are genetic changes that arise spontaneously during gametogenesis or early embryonic development, rather than being inherited from parents.

• Replication Errors: Occur at a rate of approximately $1 \times 10^{-10}$ nucleotides per cell division, even with proofreading mechanisms.

• Homogenous De Novo Mutation: All cells carry the mutation.

• Mosaic De Novo Mutation: Only some cells carry the mutation, leading to mosaicism.

Inheritance Patterns

• Familial Recessive Inheritance: Both parents are carriers; offspring inherit two mutant alleles.

• De Novo Dominant Mutation: A new mutation in a single allele can cause a phenotype if dominant.

• Loss of Heterozygosity (LOH): For a de novo recessive mutation to cause a phenotype, one parent must be heterozygous, and the other allele is lost or mutated.

Identification of De Novo Mutations

• Compare genome sequences of affected individuals to their parents (trio analysis) to identify new mutations.

• Whole-genome resequencing can pinpoint gene defects responsible for genetic diseases, even in small families.

Variables to Consider

• Isolate genetic from environmental variables.

• Exclude inherited variants to focus on de novo changes.

Summary Table: Comparison of Twin Types and Mutation Types

Aspect	Monozygotic Twins	Dizygotic Twins	Familial Mutation	De Novo Mutation
Genetic Similarity	~100%	~50%	Inherited from parents	Arises spontaneously
Origin	Single fertilized egg splits	Two separate eggs fertilized	Present in family pedigree	Not present in parents
Use in Studies	Estimate heritability	Estimate heritability	Pedigree analysis	Trio/sequence analysis

Applications and Limitations

• Pedigree and twin studies are foundational for understanding inheritance and heritability in humans.

• De novo mutation analysis is crucial for identifying causes of sporadic genetic diseases.

• Each method has limitations and must be interpreted in the context of environmental, genetic, and technical factors.

Additional info: Modern genetic studies often combine pedigree, twin, and genomic approaches to dissect complex traits and diseases in humans.