Table of Contents
Overview: What Makes Human Gene Mutations Special?
In earlier chapters you learned what mutations are in general and how they can alter genes and chromosomes. In this chapter, we focus specifically on gene mutations in humans—changes that affect single genes (or small parts of genes) and can lead to hereditary diseases, altered traits, or no noticeable effect at all.
We will not redo the full classification of mutations; instead we concentrate on:
- How gene mutations appear in human populations and families
- Why some are common and others extremely rare
- How they are detected and diagnosed
- What they mean for affected individuals and their relatives
- How they relate to human inheritance patterns, which are covered in detail elsewhere
Gene mutations in humans are often called single-gene disorders or monogenic diseases when they cause disease.
Features of Human Gene Mutations
Germline vs. Somatic Mutations in Humans
Gene mutations in humans can occur in:
- Germline cells (egg or sperm, and their precursors)
- Present from conception in every cell of the offspring
- Can be inherited and passed on to the next generation
- Responsible for classic Mendelian genetic diseases and many inherited cancer syndromes
- Somatic cells (all non-germ cells)
- Arise during a person’s lifetime in a specific tissue
- Not inherited by children
- Important in cancers, some mosaic disorders, and aging processes
Mosaicism occurs when a person has two or more genetically different cell populations due to a post-zygotic mutation (a mutation after the fertilized egg has begun dividing). Clinically, this may cause:
- Localized symptoms (e.g., skin patches with different pigmentation)
- Milder or atypical forms of diseases compared with people who carry the mutation in all cells
Germline-somatic differences and mosaicism are especially important in humans because:
- We cannot do controlled crosses as in model organisms
- Family histories and specialized tests are often needed to figure out whether a mutation is germline, somatic, or both (e.g., in some hereditary tumors).
De Novo (New) Mutations in Humans
A de novo mutation is a new mutation that appears in a child but is absent from the parents’ blood (and often from their germ cells as far as can be tested).
Key features in humans:
- Many severe dominant diseases (e.g., some forms of achondroplasia, many developmental syndromes) are often due to de novo mutations.
- Risk of recurrence in siblings is usually low, but not zero, because a parent may carry the mutation only in a subset of germ cells (germline mosaicism).
- De novo mutations are more likely in some genes than others and sometimes increase with parental age.
This pattern explains why some serious conditions are seen in families only once, without previous family history.
Types of Gene-Level Effects Especially Relevant in Humans
You already met the general types of gene mutations (point mutations, insertions, deletions, etc.). Here, we focus on functional consequences that are especially important in human medicine.
Loss-of-Function vs. Gain-of-Function
Loss-of-Function Mutations
A loss-of-function mutation reduces or abolishes the activity of a gene product.
- Often due to nonsense mutations, frameshift mutations, splice-site mutations, or deletions
- Typically inherited as:
- Autosomal recessive: disease appears only when both copies of the gene are nonfunctional (e.g., cystic fibrosis, many metabolic disorders)
- Occasionally autosomal dominant when:
- One functional copy is insufficient (haploinsufficiency), or
- The altered protein interferes with the normal one (dominant-negative effect)
In recessive disorders, carriers with one normal and one mutant allele are usually symptom-free but can pass the mutation to their children.
Gain-of-Function Mutations
A gain-of-function mutation gives a protein a new or enhanced activity, or causes it to be active at the wrong time/place.
- Often inherited as autosomal dominant
- Common in:
- Some skeletal disorders
- Many cancer-related genes (oncogenes)
- Triplet repeat expansions that lead to toxic proteins (e.g., Huntington’s disease)
These mutations often cannot be “compensated” by the normal copy, because the new or excessive activity itself is harmful.
Dominant-Negative and Haploinsufficiency
These concepts are important for understanding why some human diseases are dominant even though only one gene copy is mutated.
- Dominant-negative mutation
- The mutant protein blocks or disturbs the function of the normal protein (e.g., by forming defective complexes).
- Common in structural proteins such as collagens.
- Haploinsufficiency
- One normal copy does not produce enough gene product for a normal phenotype.
- Example: some developmental and heart defects.
In both situations, having one mutated allele is enough to cause disease, giving a dominant inheritance pattern.
Missense vs. Nonsense vs. Splice-Site Mutations in Human Disease
While these mutation types are general, some features are especially relevant in humans:
- Missense mutations (one amino acid changed)
- Can cause a spectrum of phenotypes from mild to severe
- Common in enzymes, receptors, and structural proteins
- Different missense changes in the same gene can cause different diseases or severities (allelic heterogeneity)
- Nonsense mutations (coding triplet changed to a stop codon)
- Lead to truncated, often nonfunctional proteins or cause the mRNA to be degraded
- Frequently result in severe loss-of-function phenotypes
- Splice-site mutations
- Affect the removal of introns from pre-mRNA
- Can lead to exon skipping, intron retention, or frameshifts
- Often under-recognized but responsible for many human genetic diseases
Patterns of Gene Mutations in Human Populations
Allelic Heterogeneity and Locus Heterogeneity
Two key features complicate the study of human gene mutations:
- Allelic heterogeneity
- Different mutations in the same gene cause a similar or related disease.
- Example: hundreds of different mutations in the CFTR gene can cause cystic fibrosis.
- Locus heterogeneity
- Mutations in different genes cause clinically similar diseases.
- Example: many different genes can cause hereditary deafness, or retinitis pigmentosa.
These phenomena mean that:
- Clinical diagnosis does not always reveal which gene is mutated.
- Genetic tests often must screen multiple genes or the entire exome/genome.
- Family-specific mutations are common.
Penetrance and Expressivity in Human Gene Mutations
Human gene mutations often show variability in how they present:
- Penetrance
- The proportion of individuals with a given mutation who actually show any clinical features.
- Incomplete (reduced) penetrance: some carriers remain symptom-free.
- A famous example is some hereditary cancer predisposition genes, where not every carrier develops cancer.
- Expressivity
- The degree or severity of symptoms in individuals who carry the same mutation.
- Variable expressivity: the same mutation can cause mild symptoms in one person and severe disease in another.
Environmental factors, modifier genes, and random developmental events contribute to these differences.
Examples of Human Single-Gene Disorders (Overview Only)
You will encounter detailed inheritance patterns and specific named diseases in later sections. Here we only sketch typical categories:
- Autosomal recessive, loss-of-function
- Many metabolic diseases (enzyme deficiencies), e.g. phenylketonuria
- Structural protein disorders where half activity is enough for carriers but not for homozygotes
- Autosomal dominant, gain-of-function / dominant-negative / haploinsufficiency
- Some skeletal dysplasias
- Many developmental syndromes
- Some familial hypercholesterolemia forms
- X-linked mutations
- Often recessive, affecting mostly males
- Classic examples include certain clotting factor deficiencies and muscular dystrophies
Later chapters will dive into X-linked recessive and autosomal genetic disorders in humans with concrete examples.
Mutations and Human Cancer
Although cancer involves many genes and is often not inherited in a simple way, gene mutations are central to its origin:
- Somatic mutations accumulate in body cells and can:
- Activate oncogenes (often gain-of-function)
- Inactivate tumor suppressor genes (usually loss-of-function)
- Disrupt DNA repair mechanisms, leading to further mutations
- Some people inherit a germline mutation in a tumor suppressor or repair gene, giving a strong predisposition to certain cancers.
- These are typically inherited as autosomal dominant predisposition, even though the cancer itself is not a classical Mendelian trait.
Here, the difference between inherited mutation (present from birth) and acquired somatic mutation (appearing in specific tissues) is crucial for understanding which cancers run in families and which do not.
Sources of Gene Mutations in Humans
You have already learned about causes of mutations in general (e.g. replication errors, radiation, chemicals). For humans, some aspects are especially important:
- Parental age effects
- Paternal age: more cell divisions in the male germline over time increase mutation rates in sperm; many de novo single-nucleotide mutations are paternal in origin.
- Maternal age is more associated with chromosomal abnormalities but can also play roles in some gene-level events.
- Mutagens in the environment
- Tobacco smoke components, UV radiation, some industrial chemicals, and certain drugs can increase mutation rates, especially leading to somatic mutations (e.g., cancers).
- Endogenous processes
- Normal DNA replication and repair occasionally make mistakes, even without environmental agents.
- Reactive oxygen species generated in metabolism can damage DNA.
While the majority of new mutations are harmless or have only small effects, some alter critical genes and lead to disease.
Detection and Diagnosis of Gene Mutations in Humans
Molecular Diagnostic Methods
Diagnostic methods applied in humans are based on techniques you learn in the genetic engineering and methods chapters, including:
- Targeted testing
- Searching for a known mutation in a specific gene when a particular disease is suspected
- Often done by PCR plus sequencing or mutation-specific assays
- Gene panels
- Simultaneous analysis of many genes involved in a group of disorders (e.g., cardiomyopathy panel, cancer predisposition panel)
- Exome or genome sequencing
- Analysis of all coding genes (exome) or the full DNA sequence (genome)
- Particularly useful for rare or atypical disorders
- Carrier screening
- Testing healthy individuals for carrier status of common recessive mutations (e.g., in some populations)
The goal is to detect specific gene mutations that explain a person’s symptoms or reveal a risk before symptoms appear.
Genetic Counseling and Ethical Aspects
In humans, the discovery of a gene mutation has consequences beyond biology:
- Genetic counseling provides:
- Information about the nature of the mutation and the disease
- Estimates of recurrence risk for future children
- Discussion of testing options for relatives
- Support for decision-making (e.g., reproductive choices)
- Ethical issues include:
- Predictive testing in healthy individuals (especially for adult-onset diseases)
- Testing of children for conditions that appear only in adulthood
- Privacy and potential discrimination based on genetic information
- Choices about prenatal or preimplantation genetic testing
Unlike model organisms, humans must be studied with strict respect for autonomy, confidentiality, and informed consent.
Gene Mutations in Humans and Evolution
Although many gene mutations in humans are harmful, some have had adaptive advantages in particular environments. Examples (without details here) include:
- Mutations that confer resistance to infectious diseases (e.g., certain blood cell mutations that affect malaria infection)
- Mutations affecting metabolism that were advantageous under specific nutritional conditions but can contribute to disease in modern environments
Thus, gene mutations in humans are not only a medical topic but also a key factor in our evolutionary history and diversity.
Summary
- Human gene mutations include both inherited germline and acquired somatic changes; both are important but have different consequences.
- Many human diseases result from loss-of-function or gain-of-function mutations, sometimes showing dominant-negative effects or haploinsufficiency.
- Allelic and locus heterogeneity, variable penetrance, and variable expressivity make human genetic diseases highly diverse and sometimes unpredictable.
- De novo mutations explain many severe diseases that appear for the first time in a family.
- Modern molecular methods allow precise detection of human gene mutations and underpin genetic counseling and many medical decisions.
- While some gene mutations cause disease, others have contributed to human adaptation and evolution.