Parental influence on human germline de novo mutations in 1,548 trios from Iceland

DNA mutations (alteration of a nucleotide base) can occur in the germline or somewhere in the body other than the germ cells (spermatozoa and ova). The former are called germ cell mutations, and the latter somatic cell mutations. It has long been known, or at least strongly suspected, that mutations in germ cells will increase as a function of age –– meaning that a 50-year-old is more likely to have had a detrimental mutation in a germ cell than a 20-year-old. Years ago, I remember that Leonid Kruglyak had estimated that, just from ionizing background radiation, a child will have on average ~320 de novo mutations that neither parent carries. Characterization of mutational processes that generate sequence diversity in the human genome is of paramount importance both to medical genetics and to evolutionary studies.

To understand how age and sex of transmitting parents affect de novo mutations in their offspring, authors [see attached article] performed whole-genome sequencing (WGS) on 1,548 Icelanders, their parents –– and, for a subset of 225, at least one child. They found 108,778 de novo mutations, both single nucleotide polymorphisms (SNPs) and insertions/deletions (indels), and they determined the parent of origin in 42,961 of these mutations. The number of de novo mutations from mothers increased by ~0.37 per year of age, which was only one-fourth of the number of mutations from fathers (~1.51 per year). The number of clustered mutations increased faster with the mother’s age than with the father’s age, and the genomic span of maternal de novo mutation clusters is greater than that of paternal ones.

The types of de novo mutation from mothers changed substantially with age, with a 0.26% decrease in cytosine–phosphate–guanine to thymine–phosphate–guanine (CpG>TpG) de novo mutations, and a 0.33% increase in C>G de novo mutations per year, respectively. Remarkably, these age-related changes are not distributed uniformly across the genome. A striking example is a 20-megabase (20-Mb) region on chromosome 8p, with a maternal C>G mutation rate that is as much as 50-fold greater than the rest of the genome. Age-related accumulation of maternal non-crossover gene conversions also mostly occurs within these regions. Increased sequence diversity and linkage disequilibrium of C>G variants within regions affected by excess maternal mutations indicate that the underlying mutational process has persisted in humans for thousands of years. Moreover, the regional excess of C>G variation in humans is largely shared by chimpanzees, less by gorillas, and is almost absent from orangutans. These really cool findings demonstrate that sequence diversity in humans results from evolving interactions between age, sex, mutation type, and genomic location.

Nature October 2o17; doi:10.1038/nature24018 [ePub]

Posted in Center for Environmental Genetics | Comments Off on Parental influence on human germline de novo mutations in 1,548 trios from Iceland

60 years ago this month, Francis Crick changed the logic of Biology

For all you History of Biology and the Gene buffs, this article [attached] is a must-read.

Sept 2o17 marks the 60th anniversary of one of the most significant lectures in the history of biology; it was given on 19 September 1957 by Francis Crick as part of a Society for Experimental Biology symposium on the Biological Replication of Macromolecules, held at University College London. Originally titled `Protein synthesis,’ the title changed to `On protein synthesis’ when it was written up for publication the following year. The lecture went much further than its title suggested: as Crick pointed out in the opening paragraph, he also addressed `the other central problems of molecular biology –– those of gene action and nucleic acid synthesis.’ This talk represented remarkable insight and predictions of the future in the field of molecular biology (even before it was defined as “a research field”).

Today Crick’s talk is often called the `central dogma’ lecture, because it was here that he first publicly presented this frequently misunderstood concept. While this was highly significant, the content of the lecture was even richer –– it also saw Crick outline his view of the nature of life and of genetic information and the source of protein folding as well as making two bold and spectacularly accurate predictions: [a] that there must exist a small `adaptor’ molecule {now known as transfer-RNA (tRNA)] that could bring amino acids to the site of protein synthesis and [b] that, in the future, scientists would be able to explore rich evolutionary sources of information by comparing sequence data. In this one brief lecture, Crick profoundly influenced how we think. In The Eighth Day of Creation, journalist Horace Judson went so far as to claim that on that day 60 years ago, Crick “permanently altered the logic of biology [2].”

PloS Biol Sept 2o17; 15: e2003243.

Posted in Center for Environmental Genetics | Comments Off on 60 years ago this month, Francis Crick changed the logic of Biology

Gene-environment interaction study of body mass index (BMI) reveals interactions between genetic factors and physical activity, alcohol consumption, and socioeconomic status

Genome-wide association studies (GWAS) are used for attempting to find genes/genetic loci associated with a phenotype (trait). The trait chosen to be studied might be height, weight or body mass index (BMI) –– or a complex disease such as schizophrenia, Alzheimer disease, or type-2 diabetes. The trait might also be efficacy or toxicity of a particular drug. These multifactorial traits are generally caused by hundreds if not thousands of genes, plus epigenetic effects, plus environmental factors. The present study focuses on gene-environment interactions of a multifactorial trait studied by GWAS.

BMI is a standardized measure of human body size that is calculated from weight and height. Twin studies have demonstrated a heritable component of BMI, and GWAS have shown that BMI is influenced by hundreds of common genetic variants. Recently, a GWAS for BMI on almost 340,000 individuals, reported 97 genetic loci associated with variation in BMI. However, only a few studies have investigated the effect of gene-environment interactions on BMI. Identification of gene-environment interactions for complex human traits poses several challenges. For instance, most GWAS of complex traits have been performed by large-scale meta-analyses of multiple cohorts, which complicate a harmonized collection of lifestyle and environmental data. Also, the contributing effects of genetic variants identified through GWAS are generally small, and differences in the effects of genetic variants between groups exposed to different lifestyle factors may be difficult to detect in smaller cohorts –– due to lack of statistical power.

In the attached paper, authors examine gene-environment interactions in almost 362,500 unrelated participants of Caucasian ancestry from the UK Biobank resource. A total of 94 BMI-associated single-nucleotide polymorphisms (SNPs) or variants –– selected from a previous GWAS on BMI –– were used to construct weighted genetic scores for BMI (GSBMI). Linear-regression modeling was used to estimate the effect of gene-environment interactions on BMI for 131 lifestyle factors related to: dietary habits, smoking and alcohol consumption, physical activity, socioeconomic status, mental health, and sleeping patterns, as well as female-specific factors such as menopause and childbirth. In total, 15 lifestyle factors were observed to interact with GSBMI, of which alcohol intake frequency, usual walking pace, and Townsend deprivation index (measure of socioeconomic status) were all highly significant (P = 1.5 x 10–29, P = 3.8 x 10–26 and P = 4.7 x 10–11, respectively). Interestingly, the frequency of alcohol consumption, rather than the total weekly amount, resulted in the significant interaction.

Not surprisingly, the FTO locus was the strongest single locus interacting with any of the lifestyle factors. However, 13 significant interactions were also observed after removing the FTO locus from the genetic score. The authors’ analyses indicate that many lifestyle factors modify the genetic effects on BMI –– with some groups of individuals having more than double the effect of the genetic score. However, the underlying causal mechanisms of gene-environmental interactions are difficult to deduce from cross-sectional data alone, and controlled experiments are required to fully characterize the causal factors.

PloS Genet Sept 2o17; 13: e1006977

Posted in Center for Environmental Genetics | Comments Off on Gene-environment interaction study of body mass index (BMI) reveals interactions between genetic factors and physical activity, alcohol consumption, and socioeconomic status

CRISPR/Cas9-edited correction of an autosomal dominant gene mutation responsible for hypertrophic cardiomyopathy (cause of sudden death in otherwise healthy young athletes)

The CRISPR/Cas9-edited correction of an autosomal dominant gene mutation (2 August 2o17 Nature paper –– reported by GEITP Sept 7; see way below and attached pdf files) now seems to be questioned by a number of other researchers in the field. Bottom Line: This controversy is not yet resolved at this time. Stay tuned. 🙂 DwN Skepticism surfaces over CRISPR human embryo editing claims

By Kelly Servick Aug. 31, 2017

When the first U.S. team to edit human embryos with CRISPR revealed their success earlier this month, the field reeled with the possibility that the gene-editing technique might soon produce children free of their parents’ genetic defects. But the way CRISPR repaired the paternal mutation targeted in the embryos was also a surprise. Instead of replacing the gene defect with strands of DNA that the researchers had inserted, the embryos appeared to use the mother’s healthy gene as a template for repairing the cut made by CRISPR’s enzyme.

But such a feat has not been observed in previous CRISPR experiments, and some scientists are now questioning whether the repairs really happened that way. In a paper published online this week on the preprint server bioRxiv, a group –– of six geneticists, developmental biologists, and stem cell researchers –– offers alternative explanations for the published results. And uncertainty about exactly how the embryos’ DNA changed after editing leaves many questions about the technique’s safety, they argue. (The authors declined to discuss the paper while it’s being reviewed for publication.)

Embryologist Shoukhrat Mitalipov of Oregon Health and Science University in Portland, who led the now-disputed experiments, released a statement saying that his team stands by its explanation. “We based our finding and conclusions on careful experimental design involving hundreds of human embryos,” it says.

In the 2 August Nature paper, Mitalipov and his collaborators showed they could bump up the efficiency of human embryo editing by inserting the CRISPR machinery earlier in development than previous experiments. When they combined healthy eggs with sperm bearing a disease-causing mutation and immediately added CRISPR, they found that 72% of the resulting embryos were free of the mutation—rather than the expected 50% that would have avoided inheriting the harmful gene anyway.

Although the researchers inserted short strands of DNA as templates for repair, the cells didn’t seem to take them up; those specific sequences were absent from the embryos. The cells must have relied instead on the nonmutated sequence in the egg donor’s DNA when making the repairs, the team concluded.

The bioRxiv response, led by developmental biologist Maria Jasin of Memorial Sloan Kettering Cancer Center in New York City and Columbia University stem cell biologist Dieter Egli, challenges that interpretation. The authors, which also include well-known CRISPR researcher and Harvard University geneticist George Church, say that the Nature paper goes against conventional wisdom about how embryos are organized early in development. Right after an egg is fertilized, the DNA from the sperm and the egg aren’t believed to be in close enough proximity to interact or share genes, they explain.

Stem cell researcher Junjiu Huang of Sun Yat-Sen University in Guangzhou, China, who led the first published study of CRISPR editing of a human embryo, isn’t on the bioRxiv paper, but shares that concern. It’s not unexpected for a cell to use its own sequences to guide repair, he notes. In his group’s study, which used nonviable embryos, a gene related to the CRISPR-targeted gene seemed to function as a template. But that gene was on the same chromosome as CRISPR’s edits. Here, the sperm and egg nuclei are seemingly too far apart to cooperate in the repairs, he says.

The preprint authors lay out two other scenarios for what Mitalipov’s team saw. [a] It’s possible that some of the embryos didn’t take up paternal DNA at all, and thus never inherited the mutation to begin with. In some in vitro fertilization procedures, embryos can occasionally start to develop from maternal DNA alone, and the study didn’t rule out this phenomenon for every embryo, they say.

They also suggest that [b] mutated paternal gene could have been snipped out of young embryos but never actually replaced with a healthy version. CRISPR’s cuts can sometimes cause chunks of DNA to be removed from the strand before the two cut ends are rejoined, they note. That would mean no detectable mutation—but it could also mean missing sections of DNA that could have unknown consequences for the embryo.

This possibility of “allele dropout” has been the subject of discussion in the field ever since the Nature paper was published, says developmental biologist Robin Lovell-Badge of the Francis Crick Institute in London. Many scientists are now waiting for a response from Mitalipov, he says.

In his statement, Mitalipov promised to “respond to [the] critiques point by point in the form of a formal peer-reviewed response in a matter of weeks.” He also urged follow-up to resolve the matter. “We encourage other scientists to reproduce our findings by conducting their own experiments on human embryos and publishing their results.”

Posted in Center for Environmental Genetics | Comments Off on CRISPR/Cas9-edited correction of an autosomal dominant gene mutation responsible for hypertrophic cardiomyopathy (cause of sudden death in otherwise healthy young athletes)

Predatory journals are even able sometimes to scam some senior scientists who should know better

GEITP emailings have frequently covered this topic of “predatory” “online, open-access” journals that have exploded in the past few years and now number more than 8,000 (some estimates are as high as 15,000). Pseudoscientific “editors” and “publishers” of predatory journals are easy to please. They will publish ANY paper –– with lit­tle regard for quality, at a fraction of the cost charged by mainstream open-access journals. These supposedly scholarly publishing entities are murky operations, making money by collecting fees while fail­ing to deliver on their claims of being open access and failing to provide services such as peer review and archiving. See attached 1-page editorial, plus a 3-page commentary with statistics. Note the incredible story that, upon realization a senior scientist had submitted a paper to one of these predatory journal, and then he had immediate removal of his article, the journal revoked his submission without paying the publishing charge) but responded that a $319 retrac­tion fee was due. Of course, such fees are unheard of at legitimate journals.

Despite abundant evidence that the bar is low, not much is known about who pub­lishes in this shady realm, and common wisdom assumes that the hazard of predatory publishing is restricted mainly to the developing world. In one famous sting, a journalist for Science sent a purposely flawed paper to 140 presumed predatory titles (and to a roughly equal num­ber of other open-access titles), pretending to be a biologist based in an African capital city. At least two earlier smaller surveys found that most authors were in India or elsewhere in Asia. Therefore, a campaign to warn scholars about predatory journals has concentrated its efforts in Africa, China, India, the Middle East and Russia.

Frequent, aggressive solicitations from predatory publishers are generally considered merely a nuisance for scientists from rich countries –– not a threat to scholarly integrity.

However, authors [attached] dispute this view. They spent 12 months characterizing nearly 2,000 biomedical articles from more than 200 journals thought likely to be predatory. More than half the corresponding authors hailed from “high- and upper-middle-income coun­tries”, as defined by the World Bank. Of the 17% of sampled articles that reported a funding source, the most frequently named funder was the U.S. National Institutes of Health (NIH). The United States produced more articles in their sample than all other countries, except India. Harvard University (with 9 articles) in Cambridge, Massachu­setts, and the University of Texas (with 11 articles across all campuses) were among the eight institutions with the most articles. It is easy to imagine other, similar institutions coming up in a different sample. The point is, the problem of predatory jour­nals is more urgent than many realize.

Authors urge that publishers, research insti­tutions, and funders should issue explicit warnings against illegitimate publishers and develop cohesive recommendations on pub­lication integrity together. Funders and research institutions should: [a] increase the funds that they make available towards open-access publication; [b] prohibit the use of funds to support predatory journal publications; [c] make sure that researchers are trained in how to select appropriate journals when submitting their work; and [d] audit where grantees, faculty members and research staff publish. When seeking promotion or fund­ing, researchers should include a declaration that their CV is free of predatory publications. Publication lists could be checked against lists such as the Directory of Open Access Jour­nals (DOAJ) or the Journal Citation Reports. Developing automated tools to facilitate the proposed audits would also be valuable.

Before approving a study, ethics com­mittees should ask researchers to declare in writing their willingness to work with their institutional resources, such as librarians, to ensure they do not submit to any journals without reviewing evidence-based criteria for avoiding these titles. If not, predatory journals will continue to erode the integrity of scientific scholarship. Substandard publications have polluted authentic electronic databases. A problem largely unknown a decade ago, there are now a roughly estimated 8,000 predatory titles that collectively ‘publish’ more than 400,000 items a year. We need to cut off the supply of manuscripts to these illegitimate outfits.

Nature 7 Sept 2o17; 549: 7 [editorial] plus 23–25

COMMENT: Dear all:
Want to share this for context. A bit long, but I found it casts the shadow of predictory (profitable) publishing ethics in the light of changing practices! Worth a read.

This from the Guardian early this summer.

Is the staggeringly profitable business of scientific publishing bad for science? | Science | The Guardian

Posted in Center for Environmental Genetics | Comments Off on Predatory journals are even able sometimes to scam some senior scientists who should know better

Obesity is a factor in enhancing metastasis of cancers; losing weight can reverse this effect

Because it is quite well known that obesity is associated with inflammatory processes, it probably comes as no surprise that obesity appears to enhance cancer metastasis. Obesity affects more than 30% of adults in the U.S. Although obesity has been associated with both increased cancer risk in the oncology clinic and onset of disease in pre-clinical models, it has not been clear whether obesity-associated inflammation also promotes cancer progression and metastasis.

It is well known that chronic inflam­mation, which can be driven by tumors or other pathophysiological conditions, create favourable conditions for metastatic seed­ing and growth. In fact, systemic alterations that modify the tissue landscape of organs that are distant to the primary tumour are an important determinant of metastatic progression. In the attached article and editorial, authors confirmed a link between obesity-associated inflammation and breast cancer metastasis by demonstrat­ing that obesity-associated lung neutrophilia enhances metastasis in a manner dependent on granulocyte macrophage colony stimulat­ing factor (GM-CSF) and interleukin-5 (IL5). Moreover, authors show this process is reversible through dietary changes asso­ciated with weight loss. The data in this publication indicate that special consideration of the obese patient population is critical for effective management of cancer progression.

Nat Cell Biol 2o17; 19: 974–???

Posted in Gene environment interactions | Comments Off on Obesity is a factor in enhancing metastasis of cancers; losing weight can reverse this effect

Genome-wide association study (GWAS) of gestational duration and spontaneous preterm birth

“Preterm birth” is defined as “birth at less than 37 completed weeks of gestation”. Prematurity used to be viewed as an “unpredictable and inevitable fact of life”. Medical efforts have thus focused on improving the consequences of prematurity rather than preventing its occurrence. This approach has resulted in improved neonatal outcomes, but it remains costly in terms of both the suffering of infants and their families and the economic burden on society. Prevention is preferred, and current research is being directed toward reaching this goal. Another problem is that the world’s preterm birth rate has been consistently rising. In 2006, preterm births constituted ~13% of live births in the United States, an increase of 20% since 1990 (when it was ~10.4%). Trends in most other high-income countries are similar to those in the United States.

According to estimates by the World Health Organization, among the 130 million infants born each year worldwide, 8 million die before reaching their first birthday. In the U.S. 17–34% of these infant deaths are attributable to prematurity, and only about half the cases of prematurity result from identifiable causes. Among the reasons, other than iatrogenic [i.e. caused inadvertently by a physician, surgeon, medical treatment, or diagnostic procedure] preterm delivery, are maternal conditions –– such as preeclampsia and fetal distress. However, in the past decade, the number of preterm Caesarean sections performed, regardless of gestational age, has increased by 33 to 50%, without a similar change in maternal risk profiles. This pattern suggests a lowering of the “requirements” for preterm Caesarean delivery. Other antecedents of preterm birth include multiple gestations arising from assisted reproductive technologies involving implantation of multiple embryos and advanced maternal age. In addition, surgical intervention for management of cervical intra-epithelial cancer, or more invasive lesions, is associated with an increased risk of preterm birth by a factor of approximately two.

Despite evidence that genetic factors contribute to duration of gestation and risk of preterm birth, robust associations with genetic variants have not been identified until now. Authors [see the attached elegant article and editorial] used large data sets that included gestational duration to determine possible genetic associations. They performed a genome-wide association study (GWAS) in 43,568 women of European ancestry using gestational duration as a continuous trait, and term vs preterm (<37 weeks) birth as a dichotomous outcome. They examined samples from three Nordic data sets (involving a total of 8,643 women) to test for replication of genomic loci that had significant genome-wide association (P <5.0 x 10–8) or an association with suggestive significance (P <1.0 x 10–6) in the discovery set. Four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. [EBF1 = early B-cell factor-1; EEFSEC = eukaryotic elongation factor, selenocysteine-tRNA specific; AGTR2 = angiotensin II receptor type-2; WNT4 = WNT family member-4, one of a group of highly conserved signal transduction pathways that pass signals into a cell through cell surface receptors]. Functional analysis showed that an implicated variant in WNT4 alters binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets [ADCY5 = adenylate cyclase-5; RAP2C = member of the RAS oncogene family]; these variants also showed genome-wide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genome-wide significance. An analysis of mother–infant dyads suggested that these variants act at the level of the maternal genome. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control –– support their mechanistic involvement. For some of us interested in selenite (HSeO3–) uptake [Oncotarget 2016; 7: 35327], this study provides a whole new horizon of research proposals with regard to the ZIP8 transporter that has been shown to move selenium into the cell. N Engl J Med 6 Sept 2o17; DOI: 10.1056/NEJMoa1612665 & editorial (preprint)

Posted in Center for Environmental Genetics | Comments Off on Genome-wide association study (GWAS) of gestational duration and spontaneous preterm birth

How to write a sincere-sounding (yet cleverly deceptive) Letter of Recommendation ; )

Just about every one of us has had to deal with “that problematic Letter of Recommendation” –– when it becomes time for your undergrad student or technician or senior staff member or grad student or postdoc to “move on” to a new job, and the Letter should be honest and sincere, even if the person moving on is not very competent.

So, the Letter must sound sweet and inoffensive –– even if the person being recommended is extremely underwhelming. Otherwise, if that person finds out about your Letter, he/she may become angry with you and/or threaten you with a law suit (or even bodily harm or a death threat).

So, below I’ve listed some suggestions as to how to write a sincere-sounding (yet cleverly deceptive) Letter of Recommendation… 😉

Linguistic humor, Ambiguous recommendations

If you have to write a letter of recommendation for a disgruntled employee, or inferior/mediocre/incompetent employee that is leaving your lab or office group, here are a few suggested phrases:

Lexical ambiguity

For a chronically absent employee

“A man like him is hard to find.”

For a dishonest employee

“He’s an unbelievable worker.”

For a lazy employee

“You would indeed be fortunate to get this person to work for you.”

For the office drunk

“Every hour with him was a happy hour.”

Structural ambiguity

For a chronically absent employee

“It seemed her career was just starting to take off.”

For a dishonest employee

“Her true ability was deceiving.”

For a stupid employee

“I most enthusiastically recommend this candidate with no qualifications whatsoever.”

For the office drunk

“He generally found himself loaded with work to do.”

Scope ambiguity

For an employee who is not worth further consideration as a job candidate

“All in all, I cannot say enough good things about this candidate or recommend her too highly.”

For an employee who is so unproductive that the job is better left unfilled

“I can assure you that no person would be better for the job.”


For a lazy employee

“She could not care less about the number of hours she has to put in.”

For an employee who is not worth further consideration as a job candidate

“I would urge you to waste no time in making this candidate an offer of employment.”

For a stupid (or stubborn) employee

“There is nothing you can teach a man like him.”

Posted in Center for Environmental Genetics | Comments Off on How to write a sincere-sounding (yet cleverly deceptive) Letter of Recommendation ; )

Prevention of newborn infections and systemic sepsis by using probiotics in an India rural population

“Sepsis” is a clinical syndrome characterized by systemic inflammation and circulatory compromise initiated by an infection. For those of us who have experienced working in newborn and premie nurseries, especially in county hospitals or rural settings, we know well that sepsis is a major cause of neonatal morbidity and mortality, with case fatality rates ranging from 5 to 60% –– even with antibiotic treatment. In 2o13, of the 6.3 million children worldwide who died before the age of five years old, 2.76 million were in the neonatal period, with the bulk of these in developing countries. More than 600,000 of these neonatal deaths (22%) were due to possible severe bacterial infection alone.

Whereas the term ‘sepsis’ in the developed world refers to culture-confirmed bacterial or fungal infection, it is often used interchangeably with “possible severe bacterial infection” in the developing-world setting. Lacking culture and other diagnostic facilities, all infections (including viral) are grouped into one category, and modalities for the empirical management of neonatal sepsis are unambiguous. Although the death rate of children worldwide (1–59 months) decreased by 3.4% annually from 1990 to 2012, neonatal mortality in that period only dropped by 2% per year6. In addition to prematurity, sepsis (37%) and pneumonia (5%) continue to be major contributors to deaths in the neonatal period.

No efficient means of sepsis prevention is currently available. In the attached article and editorial, authors describe a randomized, double-blind, placebo-controlled trial of an oral synbiotic preparation (Lactobacillus plantarum plus fructo-oligosaccharide) in rural Indian newborns. They enrolled 4,556 infants that were at least 2,000 g (4.4 lb.) at birth, at least 35 weeks of gestation, and with no signs of sepsis or other morbidity, and monitored them for 60 days. They found a significant decrease in the primary outcome (combination of sepsis and death) in the treatment group [risk ratio (RR) = 0.60; 95% confidence interval 0.48–0.74], with few deaths (4 placebo, 6 synbiotic). Significant reductions were also observed for culture-positive and culture-negative sepsis and lower respiratory tract infections. These results suggest that a large proportion of neonatal sepsis in developing countries could be effectively prevented using a synbiotic preparation containing L. plantarum bacterial to help support the gut microbiome in newborn children.

Nature 24 Aug 2o17; 548: 407–412 [full article] and pp 404–405 [News’N’Views editorial]

Posted in Center for Environmental Genetics | Comments Off on Prevention of newborn infections and systemic sepsis by using probiotics in an India rural population

CRISPR/Cas9-edited correction of an autosomal dominant gene mutation responsible for hypertrophic cardiomyopathy (cause of sudden death in otherwise healthy young athletes)

This is a follow-up of the layman’s article that GEITP previously shared on Aug 3 [from The New York Times, see below]. To reiterate, autosomal dominant mutations are inherited (from parent to child) as a single copy of a defective gene, thereby producing the full-blown affliction in the offspring. The mutated MYBPC3 gene causes hypertrophic cardiomyopathy (HCM); because of its delayed manifestation, this mutation escapes natural selection and is virtually always transmitted to the next generation. Consequently, the frequency of such a founder mutation in particular human populations is very high. For example, the MYBPC3 mutation is found at frequencies ranging from 2% to 8% in major Indian populations.

HCM is a myocardial disease characterized by left ventricular hypertrophy, myofibrillar disarray and myocardial stiffness; it has an estimated prevalence of 1:500 in adults and manifests clinically with heart failure. HCM is the commonest cause of sudden death in otherwise healthy young athletes. HCM, while not a uniformly fatal condition, has a tremendous impact on the lives of individuals, including physiological (heart failure and arrhythmias), psychological (limited activity and fear of sudden death), and genealogical concerns. MYBPC3 mutations account for approximately 40% of all genetic defects causing HCM and are also responsible for a large fraction of other inherited cardiomyopathies –– including dilated cardiomyopathy and left ventricular non-compaction. In the attached article and editorial, authors describe correction of the heterozygous MYBPC3 mutation in human preimplantation embryos, using precise CRISPR–Cas9-based targeting accuracy and high homology-directed repair efficiency by activating an endogenous, germline-specific DNA repair response.

Induced double-strand breaks (DSBs) at the mutant paternal allele were predominantly repaired using the homologous wild-type maternal gene instead of a synthetic DNA template. By modulating the cell cycle stage at which the DSB was induced, authors were able to avoid mosaicism in cleaving embryos and achieve a high yield of homozygous embryos carrying the wild-type MYBPC3 gene without evidence of off-target mutations. The efficiency, accuracy and safety of the approach presented suggest that it has potential to be used for the correction of heritable mutations in human embryos by complementing preimplantation genetic diagnosis. However, much remains to be considered before clinical applications –– including reproducibility of the technique with other heterozygous mutations.

Nature 24 Aug 2o17; 548: 413-419 [full article] and pp 398-400 [News’N’Views editorial]

Subject: Scientists Edit a Dangerous Mutation from Genes in Human Embryos

The day of “editing severe mutations out of the fertilized egg (zygote)” is here. The CRISPR/Cas9 editing must be done before the zygote divides beyond the eight- or sixteen-cell stage (after which differentiation into specialized cell types and tissues begins). This article (from New York Times) precedes the scientific article that will appear soon in Nature.

For clinical geneticists wondering which gene has been edited –– the detrimental mutation “repaired” is a defective variant allele of MYBPC3 (myosin-binding protein C3, cardiac), and it is inherited as an autosomal dominant trait, meaning that one out of two children from parents one of whom carries this mutation will be affected with a serious life-threatening disease called hypertrophic cardiomyopathy. DwN

Posted in Center for Environmental Genetics | Comments Off on CRISPR/Cas9-edited correction of an autosomal dominant gene mutation responsible for hypertrophic cardiomyopathy (cause of sudden death in otherwise healthy young athletes)