Inheritance in Humans

Overview

Human inheritance follows the same basic principles as in other organisms (Mendelian laws, chromosome theory), but has some special features and limitations. In humans, inheritance is mainly studied indirectly, by observing families and populations rather than by performing controlled crosses. This chapter focuses on what is specific to humans: the structure of human karyotypes, patterns of inherited traits, and how family trees (pedigrees) are analyzed.

The Human Karyotype

Humans are diploid organisms with:

46 chromosomes in most body cells
Organized into 23 pairs

22 pairs of autosomes (chromosomes 1–22)
1 pair of sex chromosomes (XX or XY)

Gametes (egg cells and sperm cells) are haploid:

23 chromosomes (one of each pair)
Eggs always carry an X chromosome
Sperm carry either X or Y

Fertilization restores the diploid number and determines genetic sex (XX or XY). How sex is determined genetically and how X chromosomes are inactivated is treated in the subsections on genotypic sex determination, Barr body, and Lyon hypothesis.

Why Human Inheritance Studies Are Special

In humans, classical breeding experiments are not possible. This leads to specific methodological and ethical constraints:

No controlled mating or large-scale crosses
Small numbers of offspring per family
Long generation times
Ethical limitations on experimental manipulation

Therefore, human inheritance is mainly studied by:

Pedigree analysis (family trees)
Population studies (frequency of traits and diseases)
Twin and adoption studies
Molecular genetic analyses

Pedigree Analysis in Humans

Pedigree analysis is the key method to infer inheritance patterns in humans.

Symbols in Pedigrees

Standardized symbols are used:

Square: male
Circle: female
Filled symbol: affected individual (shows the trait or disease)
Empty (open) symbol: unaffected
Half-filled: carrier (for some recessive traits, if known)
Horizontal line between a square and circle: mating
Vertical line from parents to offspring: descent
Roman numerals (I, II, III, …): generations
Arabic numbers (1, 2, 3, …): individuals within a generation

Goals of Pedigree Analysis

From a pedigree, one tries to:

Decide if a trait is:

Autosomal or sex-linked
Dominant, recessive, or X-linked recessive/dominant

Estimate the probability that certain individuals are carriers
Predict recurrence risk for future children
Distinguish inherited traits from non-genetic causes

Typical Inheritance Patterns in Humans

In humans, many traits and diseases show recognizable inheritance patterns. The subsections on gene mutations and chromosomal aberrations in humans present specific examples; here the focus is on recognizing the main modes of inheritance.

Autosomal Dominant Inheritance

A single mutated allele on an autosome is sufficient to express the trait.

Typical features in a pedigree:

Trait appears in every generation (vertical pattern)
Affected individuals usually have at least one affected parent
Both sexes are affected with similar frequency
Transmission from affected father to son is possible (rules out X-linked inheritance)
About 50% of the children of a heterozygous affected × unaffected mating are affected (on average)

Genotypes (simplified):

A = dominant disease or trait allele
a = normal allele

Cross Aa × aa:

50% Aa (affected)
50% aa (unaffected)

In humans, many autosomal dominant conditions are due to heterozygosity (Aa). The homozygous state (AA) is often very severe or lethal and therefore rare.

Autosomal Recessive Inheritance

The trait is expressed only when both alleles are mutated.

Typical pedigree features:

Trait often skips generations (horizontal pattern: affected siblings, unaffected parents)
Parents of affected individuals are usually unaffected carriers
Both sexes affected equally
More frequent when parents are related (consanguinity), because they are more likely to carry the same rare allele

Genotypes:

a = recessive disease allele
A = normal allele

Typical cross of two carriers Aa × Aa:

25% AA (unaffected, not carriers)
50% Aa (unaffected carriers)
25% aa (affected)

This 25% risk for each child is fundamental in genetic counseling for autosomal recessive diseases.

X-Linked Recessive Inheritance

The mutated gene is located on the X chromosome and behaves recessively. This gives a characteristic sex bias because males have only one X chromosome.

Key features:

Much more common in males than females
Affected males usually born to unaffected carrier mothers
No father-to-son transmission (fathers pass Y to sons, not X)
All daughters of an affected male are at least carriers
Carrier females have a 50% risk of transmitting the mutant allele to each son (affected) and to each daughter (carrier)

Genotypes (simplified, X^a = recessive disease allele, X^A = normal X):

Male: X^aY (affected), X^AY (unaffected)
Female: X^aX^a (affected), X^aX^A (carrier), X^AX^A (unaffected)

Example cross: carrier female X^AX^a × unaffected male X^AY:

Sons: 50% X^AY (healthy), 50% X^aY (affected)
Daughters: 50% X^AX^A (healthy), 50% X^AX^a (carriers)

The details and medical examples are discussed in the section on X-linked recessive disorders.

X-Linked Dominant and Y-Linked Inheritance (Overview)

Some traits are:

X-linked dominant:

Affected fathers pass the trait to all daughters but no sons
Affected mothers can pass the trait to sons and daughters

Y-linked (holandric):

Only males are affected
Trait passes from father to all sons

These forms are less common than the classical autosomal modes in human disease but are conceptually important.

Special Features in Human Inheritance

Complex and Multifactorial Traits

Many human characteristics (e.g., height, body weight, blood pressure, risk for common diseases like type 2 diabetes) do not follow simple Mendelian ratios. They are:

Influenced by many genes (polygenic inheritance)
Strongly modulated by environmental factors (nutrition, lifestyle, etc.)

These traits show:

Continuous variation in populations (a gradient rather than discrete categories)
Often a “threshold” behavior in disease: risk rises with total genetic and environmental load until a disease manifests

While the general idea of continuous and discontinuous variation is treated elsewhere, in humans multifactorial inheritance explains why family history can increase risk without guaranteeing disease.

Penetrance and Expressivity

Human pedigrees often deviate from ideal Mendelian patterns because of:

Incomplete penetrance:

Not all individuals with a disease allele express the phenotype
An autosomal dominant trait may “skip” a generation

Variable expressivity:

The same mutation can cause different degrees of severity or slightly different symptoms in different individuals

This is especially relevant in genetic counseling: carrying a mutant allele does not always mean the same outcome for everyone.

New Mutations and Germline Mosaicism

In humans:

Some diseases frequently arise from new mutations in the germ cells of parents (de novo mutations), often associated with:

High mutation rates in very large genes
Higher paternal age, because sperm precursor cells divide many more times than egg precursor cells

Germline mosaicism:

A mutation occurs early in the development of a parent, affecting only some germ cells
The parent is healthy (no mutation in most body cells) but can have more than one affected child

These phenomena explain sporadic occurrences of genetic diseases without a clear family history.

Imprinting and Parent-of-Origin Effects (Overview)

In a few human disorders, it matters whether a gene comes from the mother or the father (genomic imprinting). For such genes:

One copy (maternal or paternal) is epigenetically silenced
A mutation in the active copy leads to disease, depending on the parent of origin

This produces unusual inheritance patterns compared to simple Mendelian expectations.

Hemizygosity and Sex Chromosomes in Humans

Because males have XY:

They are hemizygous for X-linked genes: each gene on the X chromosome has only one copy
Recessive X-linked alleles are expressed in males with no “backup” allele

X inactivation in females (Lyonization) balances gene dosage between sexes but creates genetic mosaics at the cellular level (different cells inactivate different X chromosomes), which can modulate the expression of some X-linked traits.

Twin and Family Studies in Human Genetics

In humans, twin and adoption studies provide insight into the hereditary component of traits.

Monozygotic (identical) twins:

Share (almost) all genes

Dizygotic (fraternal) twins:

Share on average 50% of their segregating genes, like ordinary siblings

If:

A trait is much more concordant (more often present in both members) in monozygotic than in dizygotic twins, it suggests a strong genetic component.
Similarity between adopted children and their biological vs. adoptive parents reveals the relative influence of genes and environment.

These approaches are particularly important for multifactorial human traits and behaviors.

Human Inheritance and Genetic Counseling

Because humans plan families and medical decisions, inheritance patterns have direct practical relevance.

Genetic counseling uses:

Family history and pedigree analysis
Knowledge of inheritance modes (autosomal dominant/recessive, X-linked, etc.)
Population frequencies of disease alleles
Molecular genetic tests, when available

Goals:

Explain the mode of inheritance to the family in understandable terms
Estimate recurrence risks for future children
Discuss available diagnostic and therapeutic options
Support informed, autonomous decision-making

Ethical and psychosocial aspects are central in human genetics and distinguish it from genetics in model organisms.

Summary

Human inheritance follows the same basic genetic rules as in other species but shows specific characteristics:

A defined karyotype with 46 chromosomes and XX/XY sex determination
Reliance on pedigree, twin, and population studies rather than controlled crosses
Typical inheritance patterns (autosomal dominant, autosomal recessive, X-linked) recognizable from family trees
Complex, multifactorial traits where many genes and environment interact
Special phenomena such as incomplete penetrance, variable expressivity, new mutations, and imprinting
Close connection to medicine and genetic counseling, linking theoretical genetics to concrete decisions in human lives.