Dear Members, Family and Friends:
We are on the countdown – the month of March is here already, to AAHGS 39th Annual Conference in Philadelphia at the Valley Forge Casino Resort, 1160 1st Avenue, King of Prussia, PA 19406 on the dates of October 11 – 13, 2018.
Are You In – Registered and Excited as We Are to Attend? Here’s the link to registered for the conference – so claim your spot. The host, Family Quest Chapter is well into planning to make sure we have an awesome time. Let’s show our support by attending AAHGS 39thAnnual Conference; after all we’re family and connected in some way!
Share the experience of our conference perhaps with someone who has never attended before and also take pleasure while you’re there in the network opportunities by exchanging information with attendees from various places, near and far.
Don’t delay, register for the conference and book your room reservations.
2018 Conference Committee
A Genome Looks Like This
Visitors to the Genome exhibition are frequently intrigued by the Genome Ball, a three-dimensional model of the human genome that represents a creative synthesis of scientific knowledge and technical innovation. For students and adults raised on clinically produced karyotypes – those artificially arranged pairs of X-shaped chromosomes photographed during cell division – the Genome Ball will challenge all their previous (mis)conceptions and show the human genome in a new light.
How did we first begin to grasp the structure of the nucleus? It all began in 1682 when Anton van Leeuwenhoek, a fabric merchant in the Dutch city of Delft, examined blood cells of fish. Leeuwenhoek used a microscope with lenses he’d ground himself, and reported his observations in a letter to the Royal Society:
I came to observe the blood of a cod and of a salmon, which I also found to consist of hardly anything but oval figures … it seemed to me that some of them enclosed in a small space a little round body or globule …
If you’ve looked at human blood under a microscope, that description may sound odd: Mature red blood cells (RBCs) don’t contain nuclei – do they? You’re right! However, the RBCs of fish (and amphibians and reptiles) do indeed have nuclei, and Leeuwenhoek was the first to describe them. Nevertheless, the Royal Society wasn’t blown away by his letter (after all, how much could a business man with “little fortune and no formal education” know about science?). The “little round body or globule” remained nameless for the next 150 years.
Then, in 1831, the Scottish botanist Robert Brown was studying plant fertilization when he noticed that pollen moved in and out of “ovals” in the plant cells. He called each oval a “nucleus,” a Latin word meaning “nut” or “kernel” – a bit like a black walnut surrounded by its thick green hull. Not only did Brown’s name stick, but his 1833 paper even suggested that the nucleus was probably involved in fertilization and the development of embryos.
The next step in our nuclear narrative was taken by Friedrich Miescher, a Swiss physician who extracted and isolated a previously unknown substance from pus-soaked bandages at the hospital where he worked. White blood cells, a major constituent of pus, have very large nuclei, and Miescher correctly concluded that the substance came from those nuclei. He called it “nuclein.” Today we call it DNA.
Although the fine points of cell division were still unexplained, scientists in the early 1900s were eager to learn the number of chromosomes in human cells. However, counting the number of human chromosomes during cell division turned out to be quite a challenge. Even when chromosomes were lined up on the “midline” of a cell, scientists’ counts ranged from 16 to 36.
Evidently, Hans von Winiwarter got tired of these wide-ranging approximations. Using the best microscopes available to him in 1912, he produced early karyotypes by capturing and fixing human cells at the moment of cell division. Despite his best efforts, Winiwarter’s counts ranged from 46 to 49; and while noting correctly that women have two X chromosomes, he mistakenly concluded that males had only one X and no Y. For the next 40+ years, students were generally taught that human cells contained 48 chromosomes.
Finally, in 1956, the correct value of “46” was confirmed – 22 pairs of autosomes and 1 pair of sex chromosomes in human cells other than eggs or sperm. It’s surprising to learn that Watson & Crick had published their model of DNA’s structure, opening the world of modern genetics, several years before the number of human chromosomes was firmly established!
By the end of the 20th century, knowledge of DNA structure and the mechanisms of cell division had advanced dramatically. Yet, based on their school textbooks, most people still tended to picture chromosomes as the condensed “X-shaped” bodies seen in karyotypes. DNA was known to uncoil between cell divisions, but it was hard to imagine how such long straggling threads (more than 2 meters, or 6 feet, per cell) could pack into a nucleus only 6/1,000,000 of a meter in diameter (smaller than the diameter of a human hair).
Eventually, studies showed that DNA decreases in length when regions of about 166 base pairs wrap like twine around small proteins to form complexes known as nucleosomes . A short stretch of non-wound DNA falls between each nucleosomal unit, the result looking a bit like a string of beads. In such a configuration, a 1-meter (3-foot) strand of DNA is reduced to 14 cm (about 6 inches). This shortened strand then coils even more, until an X-shaped chromosome in a dividing cell measures roughly 1/10,000 the length of the DNA strand it contains!
So what does the 3-dimensional model of the nucleus, as seen in the Genome Ball, have to do with all this?
One of the most important discoveries in genome biology has been the demonstration that genomes are non-randomly organized in the nucleus.
Even though chromatin looks like long straggly threads, it is amazingly well organized: Thanks to the organized coiling of chromatin, genes are able to interact with the DNA regions that regulate them.
The genome is organized into “distinct regions of open and closed chromatin regulatory domains,” explains Dr. Laura Elnitski, senior investigator at the National Human Genome Research Institute (NHGRI) of the National Institutes of Health. Put more simply, chromatin that is less active in a given cell type, or chromosomes containing few genes, are located just inside the nuclear membrane; but more active chromatin (for example, a gene coding for insulin in healthy pancreatic cells), and chromosomes carrying many genes, occupy the center of the nucleus. Overall, the nuclear location of specific genes correlates with their activity in a given cell.
Erez Aiden (who spearheaded the Genome Ball project) also discussed chromatin organization in his prize-winning essay in Science: “Loci on the same chromosome – even at opposite ends – interact more than loci on different chromosomes.” And within individual chromosomes, “open [active] chromatin interacts more with open chromatin and closed with closed,” wrote Aiden. In short: Genes have more interactions with regions on their own chromosome; and within any given chromosome, active regions group together with other active regions, while quiet or gene-poor areas group with other quiet regions.
Aiden had found a paper theorizing that long polymers – DNA is a good example – are able to form very tight coils with no knots, “a configuration known as the fractal globule.” One of the most striking characteristics of the fractal globule is that it can be folded and refolded without disturbing the rest of the condensed polymer.
The fractal globule is easy to explain to graduate students because it closely resembles the only food we can afford: ramen, said Aiden.
Uncooked, the noodles don’t contain any knots. Even when partially cooked, they don’t get tangled in the cooking pan. However, ramen noodles do become tangled after cooking, whereas chromatin stably maintains its unknotted state throughout interphase – the period between cell divisions when chromatin in the nucleus uncoils. In that condensed but non-knotted configuration, sections of chromatin that are far apart on the long strands may be brought into proximity. Thus, interactions between chromatin on the same chromosome, or between sections with similar properties or functions, are made possible by the way chromatin is organized in the interphase nucleus.
These are but a few of the innovative and complex understandings that inspired the creators of the Genome Ball (for more information about the 3-D printing of the Genome Ball displayed at the exhibition, see the feature article “Super 3D Model: How the Genome Ball Was Created” on this website). Our knowledge of the nucleus has come a long way in the 332 years since Leeuwenhoek. But, as Aiden’s Science essay concluded: “at the fringes of our maps the world is full of surprises.”
The same is certainly true of the nucleus.
Source: Unlockinglifescode.org/the-genome-ball. Access November 19, 2017, Genome Project NIH
(2) “DNA packaging: Nucleosomes and Chromatin.” Nature Education 1 (2008):26.
(3) “Regulatory and Epigenetic Landscapes of Mammalian Genomes,” Current Topics in Genome Analysis 2014. March 26, 2014.
(4) “Leeuwenhoek Sees the Cell Nucleus.” Science of Aging: Timeline of Discoveries.
(5) Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome. Science 326 (9 October 2009): 189-324.
In a move to improve diversity in genetic research, this week 23andMe will start recruiting eligible customers to participate in the creation of an African American sequencing panel for research.
With the help of a grant from the National Human Genome Research Institute, 23andMe scientists will use contributions from customers who’ve consented to participate in this research to create a reference dataset and make the de-identified genetic data available to other qualified and vetted genetic researchers at educational and research institutions around the world.
“We are very excited about this project and its potential to make a difference in people’s lives,” said the project’s Principal Investigator, Adam Auton, a 23andMe senior scientist and statistical geneticist. “This work will help address the genetic research disparities for African Americans in particular, something that has long needed attention.”
Only a fraction of the genetic research studies done to date include people with African ancestry. According to recent data focusing on this disparity, only about 19 percent of all published genetic research includes data from non-Europeans, and only about two percent are conducted on those of African ancestry. While the bias towards European studies reflects many complicated logistic, systemic, and societal issues, it has a huge impact on what scientists can determine about the genetics underlying diseases and other conditions that impact not just non-European populations but everyone. A recent study by the University of Maryland School deftly explains the implications of these disparities:
“As long as ancestry-related biases are not addressed, and most studies continue to predominantly sample from European populations, the genetics community will face challenges with implementation, interpretation and cost-effectiveness when treating minority populations.”
To help address these disparities, 23andMe is recruiting African American customers who are are willing to have their genome sequenced. Those who are interested would then be asked to complete an additional level of consent, that would allow 23andMe to add their de-identified genetic data to a library of genetic and phenotypic data. This means the library would not receive any personally identifiable information connected to the genetic and phenotypic information. This library of data is managed by the NIH and used by qualified scientific researchers.
As part of this work we will ask a subset of our African American customers, who have consented to participate in research, if they would be willing to participate and have their DNA sequenced to become part of this reference panel. Reference panels are important because they allow scientists to improve the accuracy of genome wide association studies, which drive much of genetic research conducted today.
When a customer of 23andMe sends in their saliva sample, they are genotyped at hundreds of thousands of sites that are known to vary between individuals. However, there are tens of millions of variable sites in the genome that are not genotyped. By having access to a large number of fully sequenced genomes — a sequence panel — researchers are able to use “genotype imputation” to infer or predict the genotypes at these unobserved positions. Much like a code breaker filling in missing letters in a message, scientists — using algorithms and data from whole genome sequences panels — can predict, or impute, the missing letters of genetic data. Having a sequence panel like this gives researchers a tool to study conditions that are specific to African Americans.
Ultimately, the sequence panel data will be shared with the NIH, who will make it available to other researchers. This in turn will expand scientists’ ability to make genetic discoveries for African Americans and help build a broader understanding of how genetics influence diseases and traits across multiple populations.
This is the latest in a number of efforts by 23andMe to help alleviate some of the existing disparities in genetic research. Last year, 23andMe was awarded another NIH grant to use “admixture mapping” as a means to improve the detection of disease-causing genetic variants among people of African, Latino and Asian ancestry. In 2011, 23andMe launched its Roots into the Future® project to study the genetics of disease specific to African Americans. The African Genetics Project is a part of this growing effort to improve our knowledge of African genetic diversity.