Development Mutations May Be Present in Only One of Monozygotic Twins

By Marilynn Larkin

January 15, 2021

NEW YORK (Reuters Health) - Although the genomes of monozygotic twins are often assumed to be identical, new research has found that mutations may be present at birth in one "identical" twin, but not the other.

The findings have important research implications, because previously, any differences between identical twins were assumed to be due to environmental - not genetic - factors, researchers say.

"It turns out that a fair amount of devastating diseases of early childhood are caused by de novo mutations that you find in children, but not the parents," Dr. Kari Stefansson of deCODE genetics in Reykjavik told Reuters Health in a video call. "Similarly, the mutations we looked at that affect one identical twin but not the other fall into this category of de novo mutations."

"If you think about autism - identical twins raised apart where one develops autism and the other does not - the classical interpretation is that the difference is caused by the environment," he said. "But it is clear from our study that it is dangerous to jump to that conclusion before you have examined the genomes of the twins."

As reported in Nature Genetics, Dr. Stefansson and colleagues sequenced the genomes of 381 pairs of identical twins and their parents, spouses and children in order to track mutation divergence.

They found that monozygotic twins differ by 5.2 early developmental mutations, on average, and that about 15% have a substantial number of these early mutations that are specific to just one of them. Further, the work suggests that these mutations are formed in the first days of embryonic development, when the embryo consists of only several cells.

"We observed instances where a twin was formed from a single cell lineage in the pre-twinning cell mass and instances where a twin was formed from several cell lineages," the authors report. Specifically, they note, "CpG>TpG mutations increased in frequency with embryonic development, coinciding with an increase in DNA methylation."

They conclude that the role of genetic factors in shaping developmental disorders has been underestimated.

Experts not involved in the study welcomed the new research.

Dr. Anil Menon, professor of molecular genetics, biochemistry and microbiology at the University of Cincinnati College of Medicine in Ohio called the study "unique and groundbreaking."

"The gold standard for making estimates of environmental versus genetic contributions to variance in a trait has been the comparison of data from cohorts of monozygotic twins ('identical') with cohorts of dizygotic twins ('non-identical'). Statistical analysis is then used to estimate the genetic contribution to variance in the trait (heritability)," he told Reuters Health by email.

"The novelty of this study is the demonstration that monozygotic twins themselves have a certain intrinsic variability in their genomes, and therefore previous studies using comparison of monozygotic and dizygotic twins might actually be underestimating the contribution of genetics in variation of the trait being studied," he said.

"There may be a far-reaching impact of the study on hundreds of clinical studies that have already been reported in the literature," he added, "as it could mean a re-evaluation of the fundamental statistical models that have been used to estimate genetic contributions to variations in disease severity."

Dr. Kjersti Aagaard, a maternal-fetal medicine specialist at Texas Children's Pavilion for Women and vice chair of research in the department of obstetrics and gynecology at Baylor College of Medicine in Houston called the study "heroic and very exciting."

What makes it heroic, she said, "is the detective work that the research team undertook to identify where these genetic differences actually arose from, and the extent to which they were observed in the many different tissue types that make up our human bodies - including our own eggs and sperm."

Rather than negate the effects of environmental influences, she told Reuters Health by email, the findings "reinforce the importance of understanding the combinatorial effect of gene mutations and environmental exposures."

Dr. Nancy Segal, professor of psychology at Cal State University, in Fullerton, added in an email to Reuters Health, "Evidence of early mutational difference is not surprising; what is surprising are the many different categories of mutational concordance and discordance - and there are likely to be more. Perhaps researchers can no longer classify twins as just MZ or merely organize them based on chorionicity (shared/non-shared)."

Dr. Stefansson and most of his coauthors are employed by deCODE genetics/Amgen.

SOURCE: Nature Genetics, online January 7, 2021.