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Developmental biology - Genes

3 Genes, found only in humans, influence brain size

Three new genes arose in hominids just before a dramatic increase in brain size. All are associated with neurological disorders...

A set of three nearly identical genes found only in humans appear to play a critical role in the development of our large brains, according to a study led by researchers at the University of California, Santa Cruz.

The genes appeared between 3 and 4 million years ago, just before the period when our human ancestors' fossils reflect a dramatic brain increase. In modern humans, the genes are involved in genetic defects associated with neurological disorders.

Published May 31 in Cell, the study represents more than five years of work to characterize the genes, their role in neurological development, and their evolutionary origins. They belong to an ancient family of genes known as Notch genes, first discovered in fruit flies and named for a genetic defect causing notched wings.
"This is a family of genes that goes back hundreds of millions of years in evolutionary history and is known to play important roles in embryonic development. To find that humans have a new member of this family that is involved in brain development is extremely exciting,"

David Haussler PhD, Professor, Biomolecular Engineering, Scientific Director, Genomics Institute, University of California at Santa Cruz, USA and senior author.

The genes are human-specific Notch genes and located on the long arm of chromosome 1 at a location implicated in genetic defects. Large segments of DNA at this location are either duplicated or deleted, leading to neurological disorders known collectively as 1q21.1 deletion/duplication syndrome.

• Deletions are often associated with microcephaly (abnormally small head size) and autism.
• Duplications are often associated with macrocephaly (abnormally large head size) and schizophrenia.

These new human-specific Notch genes are derived from NOTCH2, one of four previously known mammalian Notch genes, through a duplication event that inserts an extra partial copy of NOTCH2 into the genome. This happened in an ancient ape ancestor common to humans, chimpanzees, and gorillas.
The partial duplicate was a nonfunctional "pseudogene" version which can still be found in chimp and gorilla genomes today. In the human lineage, however, this pseudogene was "revived" when additional NOTCH2 DNA was copied into its place, making it a functional gene. This new gene was then duplicated several more times, resulting in four related genes known as NOTCH2NL genes, and found only in humans.

One of the four NOTCH2NL genes appears to be a nonfunctional pseudogene, but the other three (NOTCH2NLA, NOTCH2NLB, and NOTCH2NLC) are active genes that direct production of truncated (shortened) versions of the original NOTCH2 protein. Notch proteins signal between and within cells. In many cases, the Notch signaling pathway regulates differentiation of stem cells in developing organs throughout the fetus, telling stem cells when to become mature heart cells or neurons for example.
"Notch signaling was already known to be important in the developing nervous system," explains senior author Sofie Salama, a research scientist at UC Santa Cruz. "NOTCH2NL seems to amplify Notch signaling, which leads to increased proliferation of neural stem cells and delayed neural maturation."

NOTCH2NL genes are especially active in the pool of neural stem cells thought to generate most of our cortical neurons. By delaying their maturation, the NOTCH2NL genes allow for a larger pool of stem cells (called "radial glia") to build up in the developing brain, ultimately leading to a larger number of mature neurons in our neocortex — the outer layer of the mammalian brain. In humans, the neocortex hosts higher cognitive functions such as language and reasoning).
Haussler explains: "This delayed development of cortical neurons fits a pattern of delayed maturation characteristic of human development. One of our most distinguishing features is larger brains and delayed brain development, and now we're seeing molecular mechanisms supporting this evolutionary trend — even at a very early stage of brain development."

Salama noted that the new genes are just one of many factors contributing to cortical development in humans: "NOTCH2NL doesn't act in a vacuum, but it arose at a provocative time in human evolution, and it is associated with neural developmental disorders. That combination makes it especially interesting."
The DNA copying errors that created the NOTCH2NL genes in the first place are the same type of errors that cause the 1q21.1 deletion-duplication syndrome. These errors tend to occur in places on the chromosomes where there are long stretches of nearly identical DNA sequences.

"These long segments of DNA which are almost identical can confuse replication machinery and cause instability in the genome," according to Haussler. "We may have gained our larger brains in part through the duplication of these genes, but at the expense of greater instability in that region of chromosome 1, which makes us susceptible to deletion/duplication syndrome."

Long stretches of repetitive DNA also present challenges for DNA sequencing technologies. In fact, the location of NOTCH2NL in the human reference genome was not accurate when Haussler's team first started investigating it. "When we looked at the reference genome to see where NOTCH2NL was located, we found that it was near the area involved in 1q21.1 syndrome, but not part of the region that was deleted or duplicated," he adds. "This explains why the gene was not looked at before by geneticists studying the syndrome."

After researching other genome data and the 38th genome version released in late 2013 - Haussler found NOTCH2NL is located where defects occur. Haussler's team also found deletion/duplication errors increase or decrease (respectively) along with the number of NOTCH2NL copies found in an affected genome. Other duplicated or deleted genes might also be involved in deletion/duplication syndromes.

Interestingly, genetic changes do not always result in neurological disorders. In about 20 to 50 percent of affected children, the deletion/duplication syndrome is the result of a new genetic mistake,in many cases one of the parents is found to also carry the genetic defect without any apparent symptoms. According to Haussler, this is not uncommon in genetic diseases, and underscores the importance of multiple factors behind disease. "It's amazing how often we find people with what seem to be a serious genetic conditions, yet something else compensates for it," says Haussler.

Investigation of gene defects began in 2012 when Frank Jacobs, third senior author of this paper, was working with Haussler and Salama at UC Santa Cruz as a postdoctoral researcher. His project coaxed human embryonic stem cells to differentiate into neurons so that he could identify and study genes being expressed during this process. As cells develop into cortical neurons in a petri dish, they self-organize into layers as found in a miniature version of the brain cortex. Researchers call them "cortical organoids."

Jacobs compared gene expression patterns in cortical organoids being grown from embryonic human stem cells and rhesus monkey stem cells. Many genes between the two species showed differences in timing and amount of gene expression — but NOTCH2NL was exceptional. "It was screaming hot in human cells and zero in rhesus monkeys. Rhesus monkey cells just don't have this gene," Salama found. "Finding a new Notch gene in humans set us off on a long journey." said Haussler, a Howard Hughes Medical Institute (HHMI) investigator. He remembers presenting their initial findings in 2013 to scientists at HHMI. "Their general reaction was, 'Well, it's amazing if it's true, but we're not convinced yet.' So we spent the next five years working to convince everybody."

The development of the CRISPR/Cas9 system for making genetic modifications provided a crucial tool in their work. Salama's team used it to delete NOTCH2NL genes from human embryonic stem cells. Cortical organoids grown from these cells accelerated their neural maturation and were smaller in size than organoids from normal cells. The researchers also inserted NOTCH2NL genes into mouse embryonic stem cells and showed that the genes promote Notch signaling and delayed neural maturation in mouse cortical organoids. "The fact that we can genetically manipulate stem cells with CRISPR and then grow them into cortical organoids in the lab, is extremely powerful," Haussler added. "My dream for decades has been to peer into human evolution at the level of individual genes and gene functions. It's incredibly exciting that we are now able to do that."
A major part of the research involved careful and precise sequencing of the region of chromosome 1 where NOTCH2NL genes are located in 8 normal individuals and 6 patients with 1q21.1 deletion/duplication syndrome. Researchers also analyzed the genomes of three archaic humans, two Neanderthals, and one Denisovan, finding in all of them the same three active NOTCH2NL genes that are present in modern humans.

Sequencing results showed that NOTCH2NL genes are variable in modern humans. Researchers identified eight different versions of NOTCH2NL. Haussler believes there are probably more. Each version has a slightly different DNA sequence, but it remains unclear what effects these differences may have. "We've found that all of them can promote Notch signaling. They behaved in subtly different ways when we tested them in cell cultures, but we have a lot more work to do before we can start to get a handle on what this means," said Salama.
Other genes involved in human brain development seem to have arisen through a duplication process similar to the creation of NOTCH2NL. A notable example is the gene SRGAP2C, which is thought to increase the number of connections between neurons. Locations in the genome where such duplications and rearrangements occur repeatedly, known as "duplication hubs," make up about 5 percent of the human genome and seem to have been important in human evolution according to Haussler.

• Missing SRGAP2 human-specific genes sequenced by using haploid hydatidiform mole DNA
• SRGAP2 duplicated three times in the human lineage ~1.0–3.4 million years ago
• One duplicate is expressed in the brain and is fixed in copy number in all humans
• The incomplete initial duplication likely antagonized the parent gene at birth

Gene duplication is an important source of phenotypic change and adaptive evolution. We leverage a haploid hydatidiform mole to identify highly identical sequences missing from the reference genome, confirming that the cortical development gene Slit-Robo Rho GTPase-activating protein 2 (SRGAP2) duplicated three times exclusively in humans. We show that the promoter and first nine exons of SRGAP2 duplicated from 1q32.1 (SRGAP2A) to 1q21.1 (SRGAP2B) ~3.4 million years ago (mya). Two larger duplications later copied SRGAP2B to chromosome 1p12 (SRGAP2C) and to proximal 1q21.1 (SRGAP2D) ~2.4 and ~1 mya, respectively. Sequence and expression analyses show that SRGAP2C is the most likely duplicate to encode a functional protein and is among the most fixed human-specific duplicate genes. Our data suggest a mechanism where incomplete duplication created a novel gene function—antagonizing parental SRGAP2 function—immediately “at birth” 2–3 mya, which is a time corresponding to the transition from Australopithecus to Homo and the beginning of neocortex expansion.

Authors: first authors of the paper are Ian Fiddes, a graduate student working with Haussler at UC Santa Cruz, and Gerrald Lodewijk, a graduate student working with Jacobs at the University of Amsterdam. Other coauthors include researchers at Stanford University, UC San Francisco, University of Washington, Broad Institute of MIT and Harvard, Medical Genetics Service in Lausanne, Switzerland, and Institute of Genetic Medicine in Newcastle upon Tyne, U.K. This work was supported by the Howard Hughes Medical Institute, U.S. National Institutes of Health, European Research Council, California Institute for Regenerative Medicine, Netherlands Organization for Scientific Research (NWO), and European Molecular Biology Organization.

Additional coverage:
Evolution of Human-Specific Neural SRGAP2 Genes by Incomplete Segmental Duplication
Authors: Cécile Charrier, Kaumudi Joshi, Jaeda Coutinho-Budd, Ji-Eun Kim, Nelle Lambert, Jacqueline de Marchena, Wei-Lin Jin, Pierre Vanderhaeghen, Anirvan Ghosh, Takayuki Sassa, Franck Polleux.

We thank B. Coe for assistance in CNV analysis and the 1000 Genomes Project for access to sequence data of the SRGAP2 loci. For DNA samples used in paralog-specific CNV screening and detailed phenotypic information of patients, we would like to thank C. Romano, M. Fichera, J. Gécz, B. de Vries, R. Bernier, the Simons Foundation, Autism Speaks, the National Institute of Mental Health, and the ClinSeq Project. We acknowledge C. Baker, L. Vives, and J. Huddleston for technical assistance, T. Brown for manuscript editing, and the laboratory of S. Fields for use of their Roche LC480. We also thank J. Akey, T. Marques-Bonet, A. Andres, S. Girirajan, and K. Meltz Steinberg for helpful discussion, as well as the laboratory of F. Polleux for comments and kindly sharing human RNA samples for expression studies. The BAC clones from the complete hydatidiform mole were derived from a cell line created by U. Surti. M.Y.D. is supported by U.S. National Institutes of Health (NIH) Ruth L. Kirchstein National Research Service Award (NRSA) Fellowship (1F32HD071698-01). X.N. is supported by an NIH NRSA Genome Training Grant to the University of Washington (2T32HG000035-16). P.H.S. is a Howard Hughes Medical Institute International Student Research Fellow. This work was supported by NIH Grants HG002385 and GM058815. E.E.E. is an investigator of the Howard Hughes Medical Institute. J.A.R. and L.G.S. are employees of Signature Genomic Laboratories, a subsidiary of PerkinElmer, Inc. E.E.E. is on the scientific advisory boards for Pacific Biosciences, Inc. and SynapDx Corp.

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Jun 7, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

Researchers studied the effects of NOTCH2NL genes in cortical organoids grown from human embryonic stem cells. Immunofluorescence staining shows markers for radial glia (GREEN) and cortical neurons (RED). Image credit: Sofie Salama PhD.

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