Nuclear atypia is a morphological abnormality noted by histology that is common and diagnostically important in cancer diagnosis, but its mechanisms are not understood. A zebrafish genetic screen for mutations that cause nuclear atypia yielded a mutant, huli hutu (hht) with a pleiotropic phenotype that included nuclear atypia in gastrointestinal cells, apoptotic nuclear fragmentation in neurons of the brain and eye, reduced head and eye size, and body curvature. The causative mutation was a frameshift in pola2, which encodes subunit B of DNA polymerase α (Pol α), that results in a premature stop codon at the 38th amino acid position of the 600 amino acid protein. Loss of function mutations of pola2 in other model organisms such as S. cerevisiae and Arabidopsis are known to cause rapid growth arrest, delay in S phase progression, and cell division defects. In contrast, hht can live up to 7dpf as a result of wild-type maternal pola2 mRNA detected in mutant eggs by allele-specific PCR. Subsequent somatic loss of wild-type mRNA results in atypical cellular morphology, abnormal mitoses, and tissue deformation in homozygous mutant larvae. This hht phenotype is strikingly similar to that observed in zebrafish with CRISPR/Cas9-mediated loss of function mutations in pola2 and other DNA polymerase α subunits, pola1, prim1, and prim2, indicating an effect that is not subunit-specific, but rather due to deficiencies in DNA polymerase activity. In support of this idea, inhibition of DNA synthesis associated with aphidicolin or hydroxyurea treatment also yielded tissue-specific hht-like phenotypes. Prolonged survival and development allows hht to demonstrate tissue-specific changes in cellular and nuclear morphology, suggesting that different tissues may have different requirements for DNA polymerase α activity during development.