Where new mutations come from: de novo variants, rates and parental age
Every child carries a few dozen DNA changes neither parent had; how often, where and in which parent they arise explains many sporadic genetic diseases.
Key facts
- The germline point-mutation rate is about 1 in 100 million bases per generation, so each newborn carries roughly 60–70 new single-base changes, usually one or none in a protein-coding region.
- Most new point mutations arise in the father: sperm precursors keep dividing throughout life, so the number of new mutations rises with paternal age.
- Some paternal-age disorders come from mutations that give sperm precursors a growth advantage (achondroplasia, Apert syndrome); they are almost always paternal in origin.
- Maternal age raises the risk of chromosome nondisjunction (trisomies), not of point mutations.
- Large genes have high new-mutation rates: about a third of Duchenne cases and about half of neurofibromatosis type 1 cases arise from new mutations.
In detail
- Mutational hotspots: methylated cytosines in CpG pairs deaminate to thymine; repeated DNA segments misalign and recombine, producing recurrent deletions and duplications (22q11.2, 16p11.2).
- A mutation after fertilisation produces mosaicism: only some cells carry it. If it reaches the gonads (germline mosaicism), healthy parents can have more than one affected child.
- Somatic mutations accumulate in every tissue with age; they drive cancer and, in blood, clonal haematopoiesis.
- Each person differs from the reference genome at about 4–5 million positions; most variants are common and harmless, and everyone carries several recessive disease alleles.
- Also called
- De novo mutations, Paternal age effect
Clinical notes
- When a dominant disorder appears in a child of healthy parents, a new mutation is the usual cause, but germline mosaicism keeps a small recurrence risk for siblings.
- Trio sequencing (child and both parents) finds de novo variants, a major cause of severe developmental disorders.
Test yourself
Think of the answer, then tap the question to see it.
Why do most new point mutations come from the father?
Sperm precursors divide continually through life, so more replication errors accumulate, and their number rises with paternal age.
Why can two children of unaffected parents have the same «new» dominant mutation?
One parent can carry the mutation in part of the gonads (germline mosaicism) without being affected.
Does advanced maternal age raise the risk of point mutations?
Mainly no; it raises the risk of chromosome nondisjunction and trisomies.
Connections
Educational information, not medical advice. For any symptom, see a health professional.
Sources: What is a gene variant and how do variants occur?: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Mosaicism (National Human Genome Research Institute (NHGRI), 2026); Copy Number Variation (CNV) (National Human Genome Research Institute (NHGRI), 2026); Somatic Cells (National Human Genome Research Institute (NHGRI), 2026).
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Representative model, for educational purposes only.