UC Irvine-led research team builds first tandem repeat expansions genetic reference maps – UCI News
Creationists assure us that creating new genetic information is impossible without magic performed by the magic creator because they have been sold some half-baked notion that genetic information follows the same laws of physics as energy, so can't be created according to the Third Law of Thermodynamics.
The fact that this is demonstrably wrong since gene duplication is readily observable doesn't stop them trotting out the same refuted claims time after time, but then to a creationist, having a claim refuted is not seen as a reason not to try to get away with it again later. You'll see this repeatedly as an apologist fraud such as William Lane Craig, Ken Ham or Michael J Behe will be comprehensively refuted in a public debate one day, only to try the self-same argument a day or two later on a different opponent in front of a different audience.
Sadly for creationists, however, this tactic leads them down a cul-de-sac where they are left arguing that DNA duplication must have been intelligently designed and, so they will also claim, evidence of intelligent design is evidence that their favourite god (and no other!) exists.
Which leaves them with nowhere to hide when science discovers that as many as 50 lethal genetic defects and disorders are directly attributable to what are called Tandem Repeat Expansions (TR expansion). They've painted themselves into a corner in which their favorite god must have deliberately created these genetic diseases:
In the context of genetics, what are Tandem Repeat Expansions? Tandem repeat expansions are a type of mutation in genetics where a DNA sequence containing repeating units of nucleotides expands in length. These repeats are typically found in non-coding regions of the genome, although they can also be present within coding regions.Now a team of researchers at the University of California at Irvine (UCI) have successfully compiled a comprehensive reference map of these TR expansions and the diseases they cause. Their work is the subject of an open access paper in Cell and a news release from UCI:
The expansion of tandem repeats can lead to various genetic disorders known as repeat expansion disorders. These disorders are caused by the abnormal expansion of repeat sequences beyond a certain threshold, which can disrupt the function of genes or regulatory elements. The severity of the disorder often correlates with the size of the repeat expansion.
One well-known example of a tandem repeat expansion disorder is Huntington's disease, which is caused by an expansion of CAG repeats in the HTT gene. Other examples include Fragile X syndrome, myotonic dystrophy, and various types of spinocerebellar ataxia.
Tandem repeat expansions are often unstable, meaning that they can change in size from generation to generation, leading to anticipation, where the disorder becomes more severe or manifests at an earlier age in subsequent generations. The underlying molecular mechanisms of tandem repeat expansions are complex and can involve processes such as DNA replication, repair, and recombination.
A research team led by the University of California, Irvine has built the first genetic reference maps for short lengths of DNA repeated multiple times which are known to cause more than 50 lethal human diseases, including amyotrophic lateral sclerosis, Huntington’s disease and multiple cancers.
The UC Irvine Tandem Genome Aggregation Database enables researchers to study how these mutations – called tandem repeat expansions – are connected to diseases, to better understand health disparities and to improve clinical diagnostics.
The study, published online today in the journal Cell, introduces the UC Irvine TR-gnomAD, which addresses a critical gap in current biobank genome sequencing efforts. Although TR expansions constitute about 6 percent of our genome and substantially contribute to complex congenial conditions, scientific understanding of them remains limited.
To build the database, the team utilized two software tools to analyze the genomic data of 338,963 participants across 11 sub-populations. Of the .91 million TRs identified, .86 million were of high enough quality to be retained for further study. It was also discovered that 30.5 percent of them had at least two common alternative forms of a gene caused by a mutation located in the same place on a chromosome.This groundbreaking project positions UC Irvine as a leader in human and medical genetics by addressing the critical gap in the ability to interpret TR expansions in individuals with genetic disorders. The TR-gnomAD advances our ability to determine how certain diseases might affect diverse groups of people based on variations in these mutations among ancestries. Genetic consulting companies can then develop products to interpret this information and accurately report how certain traits might be linked to different groups of people and diseases.
Professor Wei Li, co-corresponding author
Grace B. Bell Chair and professor of bioinformatics
Division of Computational Biomedicine
Department of Biological Chemistry
School of Medicine, University of California, Irvine, Irvine, CA, USA.
UC Irvine team members involved in the research included co-corresponding author and research assistant professor Ya Cui; Wenbin Ye, postdoctoral scholar; Jason Sheng Li, biological chemistry graduate student; and Eric Vilain, professor of pediatrics and the director of the Institute for Clinical and Translational Science. Also participating were Jingi Jessica Le, UCLA biostatistics professor, and Dr. Tamer Sallam, vice chair and associate professor at the UCLA David Geffen School of Medicine.Although we’ve successfully genotyped a substantial number of TRs, that is still just a fraction of the total number in the human genome. Our next steps will be to prioritize the integration of a greater number of high-quality TR and include more underrepresented ancestries, such as Australian, Pacific Islander and Mongolian, as we move closer to realizing personalized precision medicine.
Professor Wei Li
HighlightsI wonder if any creationists will be brave enough to go against their cult dogma and admit that new genetic information can arise naturally, so their favourite god is not responsible for these lethal genetic defects, or will it remain too important for people to believe that evolutionary changes can't arise naturally without intelligent interference, even though that paints their god as a malevolent sadist who tries to increase the suffering in the world? My money is on the latter because creationism is less about worshipping a notional god than about a relentlessly anti-science agenda as a prelude to a theocratic, far-right coup d'état.
Summary
- A biobank-scale reference of 0.86 million TRs derived from 338,963 humans
- A TR reference map for diverse ancestries, including 39.5% non-European samples
- Critical insights into the prevalence of ancestry-specific TR disorders
- An invaluable resource for interpreting TR expansions in diseases
The Genome Aggregation Database (gnomAD), widely recognized as the gold-standard reference map of human genetic variation, has largely overlooked tandem repeat (TR) expansions, despite the fact that TRs constitute ∼6% of our genome and are linked to over 50 human diseases. Here, we introduce the TR-gnomAD (https://wlcb.oit.uci.edu/TRgnomAD), a biobank-scale reference of 0.86 million TRs derived from 338,963 whole-genome sequencing (WGS) samples of diverse ancestries (39.5% non-European samples). TR-gnomAD offers critical insights into ancestry-specific disease prevalence using disparities in TR unit number frequencies among ancestries. Moreover, TR-gnomAD is able to differentiate between common, presumably benign TR expansions, which are prevalent in TR-gnomAD, from those potentially pathogenic TR expansions, which are found more frequently in disease groups than within TR-gnomAD. Together, TR-gnomAD is an invaluable resource for researchers and physicians to interpret TR expansions in individuals with genetic diseases.
Introduction
The Genome Aggregation Database (gnomAD),1 widely recognized as the gold-standard reference map of human genetic variation, has served as an essential tool for interpreting single-nucleotide variants (SNVs)1 and structural variants (SVs)2 identified in disease-association studies and clinical genetic diagnostic tests. However, there is no biobank-scale reference map for tandem repeat (TR) expansions, where an expansion refers to an increase in the number of “TR units” (i.e., consecutive repeated DNA sequences). To date, the only reference maps for TR expansions were constructed from limited samples,3,4 e.g., 3,350 individuals from the 1000 Genomes Project and H3Africa cohorts.3 This limitation clearly underscores the urgent need to develop a more comprehensive reference map of TR expansions, thereby offering a complete understanding of human genetic variation. Millions of TRs, constituting ∼6% of the human genome, have profound impacts on evolution and human disease.5 Compared with SNVs and SVs, TRs have mutation rates that are several orders of magnitude higher.6 Importantly, TR expansions are implicated in more than 50 lethal human diseases, including amyotrophic lateral sclerosis (ALS),5 Huntington’s disease,5 and multiple cancers.7 Furthermore, TR expansions captured by whole-genome sequencing (WGS) have been widely used in the diagnosis of rare diseases.8 Surprisingly, current biobank-scale resources utilizing WGS data, such as gnomAD1 and the Trans-Omics for Precision Medicine (TOPMed) program,9 have largely overlooked TR expansions. This oversight means that, despite the substantial contribution of TRs to monogenic and complex genetic diseases,5 our understanding of TR expansion spectrum at a biobank-scale remains strikingly limited.
The Malevolent Designer: Why Nature's God is Not Good
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