What does homozygous (having two copies of the same allele) mean in genetics?

Homozygosity in Genetics

Homozygosity refers to having two identical copies (alleles) of a gene at a particular locus, one inherited from each parent. 1, 2

Key Characteristics of Homozygosity

• Homozygous individuals have two identical alleles at a specific genetic locus (e.g., AA or GG), in contrast to heterozygous individuals who have two different alleles (e.g., AG) 1, 2

• Homozygosity can be described as either:

  • Homozygous dominant (two copies of the dominant allele)
  • Homozygous recessive (two copies of the recessive allele) 1

• Homozygosity can result from:

  • Random inheritance of identical alleles from unrelated parents
  • Inheritance from related parents (consanguinity) resulting in regions of homozygosity (ROH) 1
  • Uniparental disomy (inheriting both copies of a chromosome from one parent) 1

Clinical Significance of Homozygosity

Disease Expression

• For most autosomal dominant disorders, homozygotes are more severely affected than heterozygotes, demonstrating incomplete dominance 3

• The severity in homozygotes compared to heterozygotes depends on the molecular mechanism:

  • Point mutations or deletions (e.g., PAX3 in Waardenburg syndrome): homozygotes are more severely affected due to complete loss of function 3
  • Duplications (e.g., PMP22 in Charcot-Marie-Tooth 1A): homozygotes have more severe disease due to greater overexpression 3
  • Structural protein mutations: homozygotes may be similarly affected (epidermolysis bullosa simplex) or more severely affected (achondroplasia, Marfan syndrome) 3
  • Triplet repeat disorders: variable effects (more severe in Machado-Joseph disease, similar in Huntington disease) 3, 4

Regions of Homozygosity (ROH)

• Large regions of homozygosity (>3-5 Mb) may indicate:

  • Identity by descent (IBD) from a common ancestor
  • Increased risk for autosomal recessive disorders 1

• Clinical thresholds for reporting ROH:

  • 2-3% of the autosomal genome (consistent with second-cousin parentage)

  • 5% for prenatal testing

  • 10% suggests first or second-degree parental relationship 1

Homozygosity in Genetic Analysis

• Homozygosity haplotype (HH) analysis can identify shared chromosomal segments derived from common ancestors, useful for identifying disease susceptibility genes 5

• Homozygosity mapping is particularly valuable for identifying genes in autosomal recessive disorders 5

• When analyzing genetic data, it's important to distinguish true regions of homozygosity from:

  • Small segments due to suppressed recombination
  • Regions of linkage disequilibrium (identity by state)
  • Deletions that may appear as homozygous regions 1

Practical Implications

• Homozygosity for recessive disease alleles results in disease expression
• Homozygosity for dominant disease alleles typically produces more severe disease than heterozygosity
• Detection of extensive homozygosity may warrant genetic counseling and consideration of recessive disorders in diagnostic workups
• Huntington's disease is a notable exception where homozygotes and heterozygotes have similar clinical presentations 4

Understanding homozygosity is crucial for interpreting genetic test results, genetic counseling, and diagnosing recessive disorders, particularly in populations with higher rates of consanguinity.