Genetic Linkage- Sep 22

Genetic Linkage and Chromosome Mapping

Introduction to Genetic Linkage

Genetic linkage refers to the phenomenon where genes that are located close to each other on the same chromosome tend to be inherited together. This is an exception to Mendel's law of independent assortment and is a foundational concept in chromosome mapping and genetic analysis.

• Linked Genes: Genes on the same chromosome that are close together and tend to be inherited as a group.

• Independent Assortment: Genes on different chromosomes, or far apart on the same chromosome, assort independently during meiosis.

• Example: In Drosophila melanogaster (fruit fly), the genes for eye color (pr) and wing shape (vg) can be linked if they are close together on the same chromosome.

Phenotypic Ratios in Dihybrid Crosses

When two genes are unlinked, a dihybrid test cross yields a 1:1:1:1 ratio of phenotypes in the F2 generation. If the genes are linked, the ratio deviates due to reduced recombination between the loci.

• Parental Types: Offspring with the same combination of traits as the parents.

• Recombinant Types: Offspring with new combinations of traits due to crossing over.

Example Table: Expected vs. Observed Phenotypes

Phenotype	Expected (Unlinked)	Observed (Linked)
Red eyes, normal wings	709	1239
Purple eyes, short wings	709	1095
Red eyes, short wings	709	250
Purple eyes, normal wings	709	252
Total	2836	2836

Additional info: The deviation from the 1:1:1:1 ratio indicates linkage between pr and vg.

Measuring Linkage: Recombination Frequency and Map Units

The frequency of recombination between two genes is used to estimate their distance on a chromosome. This is expressed in map units (centimorgans, cM).

• Recombination Frequency (RF): The proportion of recombinant offspring among the total.

• Map Unit (cM): 1 cM corresponds to a 1% recombination frequency.

Formula:

$\text{Map Units (cM)} = \frac{\text{Number of Recombinants}}{\text{Total Offspring}} \times 100$

Example Calculation: If 44 recombinants are observed out of 400 total offspring:

$\text{Map Units} = \frac{44}{400} \times 100 = 11.0\ \text{cM}$

Genetic vs. Physical Maps

Genetic maps are based on recombination frequencies, while physical maps are based on actual DNA sequence distances. 1% recombinant progeny = 1 map unit = 1 centimorgan (cM). However, crossing over is not always random due to hotspots and cool spots on chromosomes.

Linkage Disequilibrium

Definition and Application

Linkage disequilibrium (LD) refers to the non-random association of alleles at different loci. LD is used in human genetics to map disease genes by identifying marker alleles that co-occur with disease alleles more often than expected by chance.

• Marker Alleles: DNA sequences used to track inheritance patterns.

• Application: LD mapping is crucial for identifying genetic variants associated with complex diseases.

Human Genetic Studies

Challenges in Human Genetics

Human genetic studies are more complex than animal studies due to ethical, practical, and biological constraints.

• Cannot perform controlled crosses.

• Long generation times and small family sizes.

• Multiple environmental and genetic factors influence traits.

Main Types of Human Genetic Studies

There are four main types of studies used to investigate genetic traits in humans:

1. Cross-sectional Studies: Analyze all individuals at a single time point. Pro: Large sample sizes. Con: Cannot account for differing histories or multiple influences.

2. Longitudinal (Prospective/Cohort) Studies: Follow individuals over time. Pro: Accounts for individual histories. Con: Expensive, time-consuming, and complex.

3. Randomized Controlled Trials (RCTs): Intervention studies with control groups. Pro: Gold standard for isolating single variables. Con: Expensive, limited to one variable at a time.

4. Natural Experiments/Case Studies: Includes pedigree analysis. Pro: Can isolate individual variables. Con: Small sample sizes, potential for confounding factors.

Pedigree Analysis

Pedigrees are diagrams that show the inheritance of traits across generations. They are essential for:

• Determining inheritance patterns (dominant, recessive, X-linked, etc.).

• Calculating the probability of inheriting a disease.

• Identifying mutated genes underlying a disease.

• Mapping the location of mutations using linkage and linkage disequilibrium.

Polymorphisms and Genetic Markers

Definition and Types

Polymorphisms are unique sites in the genome that can vary between individuals. They serve as genetic markers for mapping and disease association studies.

• Restriction Fragment Length Polymorphisms (RFLPs): Variation in restriction enzyme sites.

• Microsatellite Markers (SSLPs/STRs): Variation in the number of short tandem repeats.

• Single Nucleotide Polymorphisms (SNPs): Variation at a single nucleotide position.

Polymorphisms are similar to alleles:

• Homozygous Sequence A

• Heterozygous Sequence AB

• Homozygous Sequence B

Using Polymorphisms in Mapping

Polymorphisms are used in combination with linkage analysis to identify the location of disease-causing mutations. By tracking the inheritance of polymorphic markers and disease phenotypes in families, researchers can narrow down the genomic region associated with the disease.

Example Table: Types of Polymorphisms

Type	Description	Example
RFLP	Variation in restriction enzyme sites	EcoRI site present/absent
SSLP/STR	Variation in repeat length	(CA)n repeats
SNP	Single nucleotide change	A/G at a specific position

Summary

• Genetic linkage and recombination frequencies are key to mapping genes on chromosomes.

• Linkage disequilibrium is a powerful tool for mapping disease genes in humans.

• Human genetic studies require specialized approaches due to ethical and practical constraints.

• Polymorphisms serve as essential markers for genetic mapping and disease association studies.