Chitinase-3-like 1 protein (CHI3L1) locus influences cerebrospinal fluid levels of YKL-40.

Background: Alzheimer's disease (AD) pathology appears several years before clinical symptoms, so identifying ways to detect individuals in the preclinical stage is imperative. The cerebrospinal fluid (CSF) Tau/Aβ ratio is currently the best known predictor of AD status and cognitive decline, and the ratio of CSF levels of chitinase-3-like 1 protein (CHI3L1, YKL-40) and amyloid beta (Aβ) were reported as predictive, but individual variability and group overlap inhibits their utility for individual diagnosis making it necessary to find ways to improve sensitivity of these biomarkers.

Methods: We used linear regression to identify genetic loci associated with CSF YKL-40 levels in 379 individuals (80 cognitively impaired and 299 cognitively normal) from the Charles F and Joanne Knight Alzheimer's Disease Research Center.

Genetic studies of plasma analytes identify novel potential biomarkers for several complex traits.

Genome-wide association studies of 146 plasma protein levels in 818 individuals revealed 56 genome-wide significant associations (28 novel) with 47 analytes. Loci associated with plasma levels of 39 proteins tested have been previously associated with various complex traits such as heart disease, inflammatory bowel disease, Type 2 diabetes and multiple sclerosis. These data suggest that these plasma protein levels may constitute informative endophenotypes for these complex traits.

Cisplatin depletes TREX2 and causes Robertsonian translocations as seen in TREX2 knockout cells.

Cisplatin, an anticancer drug, forms DNA interstrand cross-links (ICL) that interfere with replication, whereas TREX2 is a 3'-->5' exonuclease that removes 3' mismatched nucleotides and promotes cellular proliferation. Here, we show that TREX2 is depleted in human cells derived from cancer after exposure to cisplatin but not other genotoxins including another cross-linking agent, mitomycin C (MMC), indicating a potential role for TREX2 depletion in cisplatin-induced cytotoxicity. To better understand TREX2 cellular function, we deleted TREX2 in mouse embryonic stem (ES) cells by gene targeting and find these cells exhibit reduced proliferation and gross chromosomal rearrangements including Robertsonian translocations (RbT).

HPRT minigene generates chimeric transcripts as a by-product of gene targeting.

The HPRT minigene is a selection cassette used for gene targeting in mouse embryonic stem (ES) cells and, it is unique since selection may be applied for its presence and absence. This minigene has two exon clusters separated by a small intron and splicing sequences. We find these exon clusters splice into exons from the target gene forming two different classes of chimeric transcripts.

Biochemical and cellular characteristics of the 3' -> 5' exonuclease TREX2.

TREX2 is an autonomous nonprocessive 3' --> 5' exonuclease, suggesting that it maintains genome integrity. To investigate TREX2's biochemical and cellular properties, we show that endogenous TREX2 is expressed widely in mouse tissues and human cell lines. Unexpectedly, endogenous human TREX2 is predominantly expressed as a 30-kDa protein (not 26 kDa, as previously believed), which is likely encoded by longer isoforms (TREX2(L1) and/or TREX2(L2)) that possess similar capacity for self-association, DNA binding and catalytic activity.