Molecular-modeling terms in pharmacology: ADMET, ADME and ADME-Tox

The acronym ADMET stands for absorption, distribution, metabolism, elimination, and toxicity. The word elimination may be swapped for excretion. This acronym is typically used in the context of drug design, where the relationship between the molecular structure and properties of chemical substances with pharmacokinetic, metabolic and toxicological endpoints is key in finding promising candidates to be further explored and tested as drugs. Toxicity—seen as a result of the other for processes or phenomena—is sometimes considered separatedly and the acronym ADME without a final T for toxicity is then used. Or, the notation ADME-Tox (also: ADME/Tox) is employed, visually separating the role of toxicity from the four physiological functions.

A short introduction and important links to ADMET-integrated research and associated software tools have recently been posted online. 

An acronym in genetics: SNP for single nucleotide polymorphism

In genetics, the acronym SNP stands for single nucleotide polymorphism. SNP is pronounced “snip” [1-4] .

SNPs are recognized by comparing aligned sequences of DNA. A single location along a pair of “matching” sequences, at which two nucleotides differ, constitute a SNP. In the above example, the swap of thymine (T) for adenine (A) is such a SNP.

SNPs are biological markers in the genome of humans and other life forms. SNP comparison—by using human genomes from distinct populations around the world—helps to understand genetic diversity of humans and, for example, regiospecific disease patterns and human adaption to different environments.

A recent article by Gary Styx illustrates the role of SNP in studying the historical path of human migration around the globe all the way to contemporary human diversity [5].

Keywords: bioinformatics, evolutionary anthropology, ancestry, DNA building blocks, diversity of DNA

References and more to explore
[1] An earlier SNP post on Latintos: http://golatintos.blogspot.com/2010/10/acronym-in-genomics-snp-for-single.html.
[2] Genetics Home Reference: What are single single nucleotide polymorphisms (SNPs)? [ghr.nlm.nih.gov/handbook/genomicresearch/snp].
[3] SNPedia: Single Nucleotide Polymorphism [snpedia.com/index.php/Single_Nucleotide_Polymorphism].
[4] National Human Genome Research Institute/Francis S. Collins: Single Nucleotide Polymorphisms (SNPs) [www.genome.gov/Glossary/index.cfm?id=185].
[5] Gary Styx: Traces of a Distant Past. Scientific American Winter 2013, 22 (1), 60-67.

An acronym in genetics: HAR1 for human accelerated region 1

A recent Special Collector's Edition of Scientific American is entitled What Makes Us Human. The missing question mark suggests that some knowledge exists today on what makes humans evolutionary different from closely related hominids and also from other mammals—despite nearly identical DNA blueprints. A key finding concerning this difference is presented in an exciting article by Katherine Pollard, entitled What Makes Us Different? [1]. Notice the question mark here! The discussed difference: the evolutionary change of a DNA sequence of 118 bases known as human accelerated region 1, HAR1 for short [1-4].

The name for this stretch of letters (bases) refers to the rapid change of letters (18 out of the 118 bases) in the human sequence that occurred over the last 6 million years relative to the conforming chimpanzee sequence. In contrast, comparison of this sequence between chimps, chickens and other vertebrate species over the past 300 million years reveals extremely slow changes (two out of 118 letters differing in the chimp and chicken sequence). Conclusion: the HAR1 genome region remained almost unchanged during most of the vertebrate evolution, while—throughout the dawn of humanity—it quickly acquired new and significant functions in humans, relative to the offsprings of their common chimp-like ancestors.

HAR1 does not directly encode proteins, but RNA. HAR1 is the first documented example of an RNA-encoding sequence that might have undergone positive selection (directional selection), a special mode of natural selection. Recent research suggests that HAR1 has a significant role in the development of a healthy cerebral cortex, the wrinkled outermost brain layer [1].

Many other accelerated genome regions have been predicted and identified, including HAR2, which drives limb (wrist and thumb) development and may be responsible for human dexterity [1,4], as well as a sequence within the FOXP2 gene, which is associated with speech and language development [1,5]. 

Keywords: biology, biostatistics, bioinformatics, mammalian genome, genome scanning, human-specific brain features, evolutionary anthropology.

References and more to explore
[1] Katherine S. Pollard: What Makes Us Different? Scientific American Winter 2013, 22 (1), 30-35.
[2] Katherine S. Pollard et al.: An RNA gene expressed during cortical development evolved rapidly in humans. Nature 2006, 443, 167-172. DOI: 10.1038/nature05113.
[3] Artemy Beniaminov, Eric Westhof and Alain Kroi: Distinctive structures between chimpanzee and human in a brain noncoding RNA. RNA 2008, 14, 1270-1275.
DOI: 10.1261/rna.1054608.
[4] Jeffrey Norris: What Makes Us Human? Studies of Chimp and Human DNA May Tell Us. June 28, 2010 [http://www.ucsf.edu/news/2010/06/5993/what-makes-us-human-studies-chimp-and-human-dna-may-tell-us].
Note: this post also features Katie Pollard, a biostatistician at the University of California in San Francisco, who played an important role in creating mathematical algorithms and software for comparative genomics.
[5] FOXP2: A genetic window into speech and language. [http://www.yourgenome.org/sis/evbbi/evbbi20.shtml].